Chemical compounds

ABSTRACT

This invention relates to compounds of formula (1), wherein substituents are defined in the description, that inhibit farnesylation of mutant ras gene products tough inhibition of the enzyme farnesyl-protein transferase (FPTase). The invention also relates to methods of manufacturing the compounds, pharmaceutical compositions and methods of treating diseases, especially cancer, which are mediated through farnesylation of ras.

This is a 371 of International Application PCT/GB99/04308 filed Dec. 17,1999.

This invention relates to compounds that inhibit farnesylation of mutantras gene products through inhibition of the enzyme farnesyl-proteintransferase (FPTase). The invention also relates to methods ofmanufacturing the compounds, pharmaceutical compositions and methods oftreating diseases, especially cancer, which are mediated throughfarnesylation of ras.

Cancer is believed to involve alteration in expression or function ofgenes controlling cell growth and differentiation. Whilst not wishing tobe bound by theoretical considerations the following text sets out thescientific background to ras in cancer. Ras genes are frequently mutatedin tumours. Ras genes encode guanosine triphosphate (GTP) bindingproteins which are believed to be involved in signal transduction,proliferation and malignant transformation. H-, K- and N-ras genes havebeen identified as mutant forms of ras (Barbacid M, Ann. Rev. Biochem.1987, 56: 779-827). Post translational modification of ras protein isrequired for biological activity. Farnesylation of ras catalysed byFPTase is believed to be an essential step in ras processing. It occursby transfer of the farnesyl group of farnesyl pyrophosphate (FPP) to acysteine at the C-terminal tetrapeptide of ras in a structural motifcalled the CAAX box. After further post-translational modifications,including proteolytic cleavage at the cysteine residue of the CAAX boxand methylation of the cysteine carboxyl, ras is able to attach to thecell membrane for relay of growth signals to the cell interior. Innormal cells activated ras is believed to act in conjunction with growthfactors to stimulate cell growth. In tumour cells it is believed thatmutations in ras cause it to stimulate cell division even in the absenceof growth factors (Travis J, Science 1993, 260: 1877-1878), possiblythrough being permanently in GTP activated form rather than cycled backto GDP inactivated form. Inhibition of farnesylation of mutant ras geneproducts will stop or reduce activation.

One class of known inhibitors of farnesyl transferase is based onfarnesyl pyrophosphate analogues; see for example European patentapplication EP 534546 from Merck. Inhibitors of farnesyl transferasebased on mimicry of the CAAX box have been reported. Reiss (1990) inCell 62, 81-8 disclosed tetrapeptides such as CVIM (Cys-Val-Ile-Met).James (1993) in Science 260, 1937-1942 disclosed benzodiazepine basedpeptidomimetic compounds. Lerner (1995) in J. Biol. Chem. 270, 26802 andEisai in International Patent Application WO 95/25086 disclosed furtherpeptidomimetic compounds based on Cys as the first residue.Bristol-Myers Squibb in European Patent Application EP 696593 disclosedfarnesyl transferase inhibitors having a 4-sulfanylpyrrolidine residuein the first position.

International Patent Application WO 97/17070 discloses a broad range ofcompounds which can contain an imidazole group and a methioninesubstituent. We have now discovered a narrow class of imidazolecompounds which have improved properties.

According to one aspect of the present invention there is provided acompound of Formula (1):

wherein Ar¹ represents:

R⁵ is hydrogen, C₁₋₄alkyl, phenylC₁₋₄alkyl;

R⁶ is hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl, haloC₁₋₄alkyl,dihaloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, sulfanylC₁₋₄alkyl,aminoC₁₋₄alkyl, N—(C₁₋₄alkyl)aminoC₁₋₄alkyl,N,N-di(C₁₋₄alkyl)aminoC₁₋₄alkyl or phenylC₁₋₄alkyl; m is 0,1 or 2;

R¹² and R¹³ are independently hydrogen or C₁₋₄alkyl;

Ar¹ is phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl,thiazolyl, furyl or oxazolyl, the ring being substituted on ring carbonatoms by R² and —(CH₂)_(n)R³, wherein Ar² is attached toAr¹C(R¹²)R¹³CH═CH— by a ring carbon atom; or Ar¹ is pyrrolyl, pyrazolylor imidazolyl, substituted by R² and —(CH₂)_(n)R³ (the pyrrolyl,pyrazolyl or imidazolyl rings can bear a substituent on the sp³hybridised ring nitrogen or Ar² can be attached to Ar¹(R¹²)R¹³CH═CH— bythe sp³ hybridised ring nitrogen);

R² is a group of the Formula (2):

wherein R⁷ is hydrogen or C₁₋₄alkyl, R⁸ is —(CH₂)_(q)—R¹⁰ wherein q is0-4 and R¹⁰ is C₁₋₄alkylsulfanyl, C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl,hydroxy, C₁₋₄alkoxy, carbamoyl, N—C₁₋₄alkyl carbamoyl,N,N-(diC₁₋₄alkyl)carbamoyl, C₁₋₄alkyl, phenyl, thienyl, orC₁₋₄alkanoylamino, R⁹ is hydroxy, C₁₋₆alkoxy, C₃₋₉cycloalkyloxy,heterocyclyloxy, heterocyclylC₁₋₄alkoxy or —NH—SO₂—R¹¹ wherein R¹¹represents, trifluoromethyl, C₁₋₄alkyl, phenyl, heteroaryl,arylC₁₋₄alkyl or heteroarylC₁₋₄alkyl;

or R² represents a lactone of Formula (3)

 the group of Formula (2) or (3) having L or D configuration at thechiral alpha carbon in the corresponding free amino acid;

n is 0, 1, or 2;

R³ is phenyl or heteroaryl;

or R² is a group of the Formula (4):

—CONHCH(R¹⁴)R¹⁵  Formula (4)

 wherein R¹⁴ is —(CH₂)_(q)—R¹⁵ wherein q is 0-4 and R¹⁵ isC₁₋₄alkylsulfanyl, C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl, hydroxy,C₁₋₄alkoxy, carbamoyl, N—C₁₋₄alkyl carbamoyl,N,N-(diC₁₋₄alkyl)carbamoyl, C₁₋₄alkyl, phenyl, thienyl, orC₁₋₄alkanoylamino; R¹⁴ is of the formula —CH₂OR¹⁷ (wherein R¹⁷ ishydrogen, C₁₋₄alkyl, phenyl, heteroaryl, C₂₋₅alkanoyl, C₁₋₄alkoxymethyl,phenoxymethyl or heteroaryloxymethyl), of the formula —COR¹⁸ or of theformula —CH₂COR¹⁵ (wherein R¹⁸ is C₁₋₄alkyl (optionally substituted byhalo, cyano, C₂₋₅alkanoyloxy, hydroxy, C₁₋₄alkoxy or C₁₋₄alkanoyl),phenyl, phenylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄alkyl,C₅₋₇cycloalkyl, C₅₋₇cycloalkylC₁₋₃alkyl, 2-(phenyl)ethenyl,2-(heteroaryl)ethenyl or N-methoxy-N-methylamino); or R¹³ ismorpholinoC₁₋₄alkyl, pyrrolidin-1-ylC₁₋₄alkyl or piperidin-1-ylC₁₋₄alkylwherein the morpholine, pyrrolidine and piperidine rings are optionallysubstituted by C₁₋₄alkyl or C₅₋₇cycloalkyl; or R¹³ isphenyl-1-hydroxyC₁₋₄alkyl or heteroaryl-1-hydroxyC₁₋₄alkyl;

phenyl and heteroaryl rings in R³, R⁵, R⁶, R¹¹ and R¹⁵ (including R¹⁷and R¹⁸) are independently optionally substituted on ring carbon atomsby up to three substituents selected from C₁₋₄alkyl, halogen, hydroxy,C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkanoylamino, nitro, cyano,carboxy, thiol, C₁₋₄alkylsulfanyl, C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl,C₁₋₄alkanesulphonamido, N—(C₁₋₄alkylsulphonyl)—N—C₁₋₄alkylamino,aminosulfonyl, N—(C₁₋₄alkyl)aminosulfonyl,N,N-di(C₁₋₄alkyl)aminosulfonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl,N,N-(diC₁₋₄alkyl)carbamoyl, carbamoylC₁₋₄alkyl,N—(C₁₋₄alkyl)carbamoylC₁₋₄alkyl, N,N-(diC₁₋₄alkyl)carbamoylC₁₋₄alkyl,hydroxyC₁₋₄alkyl and C₁₋₄alkoxyC₁₋₄alkyl and on ring NH groups(replacing hydrogen) by C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulfonyl,haloC₁₋₄alkyl, difluoromethyl or trifluoromethyl;

or a pharmaceutically-acceptable salt, prodrug or solvate thereof

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds ofFormula (1) defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the property of inhibiting FTPase. The synthesis of opticallyactive forms may be carried out by standard techniques of organicchemistry well known in the art, for example by synthesis from opticallyactive starting materials or by resolution of a racemic form. Similarly,inhibitory properties against FTPase may be evaluated using the standardlaboratory techniques referred to hereinafter.

The term “heterocyclyl” refers to a 5- or 6-membered monocyclic ringcontaining 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.

The term “heteroaryl” refers to a 5-10 membered monocyclic heteroarylring containing 1 to 3 heteroatoms selected from nitrogen, oxygen andsulphur.

The ring sp³ hybridised ring nitrogen in the pyrrolyl, pyrazolyl orimidazolyl rings is the ring nitrogen which can be substituted withoutbecoming quaternised i.e. the ring >NH nitrogen.

The term “halogen ” refers to fluorine, chlorine, bromine and iodine.The term “carbamoyl” refers to —C(O)NH₂. The term “BOC ” refers totert-butoxycarbonyl.

Examples of C₁₋₄alkyl include methyl, ethyl, propyl, isopropyl,sec-butyl and tert-butyl; examples of C₁₋₄alkoxy include methoxy, ethoxyand propoxy; examples of C₁₋₄alkanoyl include formyl, acetyl andpropionyl; examples of C₁₋₄alkanoyloxy include acetyloxy andpropionyloxy; examples of C₁₋₄alkylamino include methylamino,ethylamino, propylamino, isopropylamino, sec-butylamino andtert-butylamino; examples of di-(C₁₋₄alkyl)amino include di-methylamino,di-ethylamino and N-ethyl-N-methylamino; examples of C₁₋₄alkanoylaminoinclude acetamido and propionylamino; examples of C₁₋₄alkoxycarbonylinclude methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples ofC₁₋₄alkylsulfanyl include methylsulfanyl, ethylsulfanyl, propylsulfanyl,isopropylsulfanyl, sec-butylsulfanyl and tert-butylsulfanyl; examples ofC₁₋₄alkylsulfinyl include methylsulfinyl, ethylsulfinyl, propylsulfinyl,isopropylsulfinyl, sec-butylsulfinyl and tert-butylsulfinyl; examples ofC₁₋₄alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl; examples ofN—(C₁₋₄alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl;examples of N,N-(diC₁₋₄alkyl)carbamoyl include N,N-dimethylcarbamoyl andN-methyl-N-ethylcarbamoyl; examples of C₁₋₄alkanesulfonamido includemethanesulfonamido, ethanesulphonamido and propanesulfonamido; examplesof C₁₋₄alkylsulfonyl-N—C₁₋₄alkylamino includemethylsulfonyl-N-methylamino, ethylsulfonyl-N-methylamino andpropylsulfonyl-N-methylamino; examples of fluoroC₁₋₄alkyl includefluoromethyl, 2-fluoroethyl and 3-fluoropropyl; examples ofdifluoroC₁₋₄alkyl include difluoromethyl, 2,2-difluoroethyl and3,3-difluoropropyl; examples of carbamoylC₁₋₄alkyl includecarbamoylmethyl, carbamoylethyl and carbamoylpropyl; examples ofN—(C₁₋₄alkyl)carbamoylC₁₋₄alkyl include N-methyl-carbamoylmethyl andN-ethyl-carbamoylethyl; examples of N,N-(diC₁₋₄alkyl)carbamoylC₁₋₄alkylinclude N,N-dimethylcarbamoylethyl and N-methyl-N-ethylcarbamoylethyl;examples of hydroxyC₁₋₄alkyl include hydroxymethyl, hydroxyethyl,hydroxypropyl, 2-hydroxypropyl, 2-(hydroxymethyl)propyl andhydroxybutyl; examples of C₁₋₄alkoxyC₁₋₄alkyl include methoxyethyl,ethoxyethyl and methoxybutyl; examples of sulfanylC₁₋₄alkyl includesulfanylmethyl, sulfanylethyl, sulfanylpropyl; and examples ofN—(C₁₋₄alkyl)aminoC₁₋₄alkyl include N-methyl-aminomethyl andN-ethyl-aminoethyl.

Examples of 5- or 6-membered heteroaryl ring systems include imidazole,triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole,oxazole, isothiazole, thiazole and thiophene.

Preferably the NH group in imidazole is unsubstituted or substituted byC₁₋₄alkyl. Examples of heterocyclyl rings include pyrrolidinyl,morpholinyl, piperidinyl, dihydropyridinyl and dihydropyrimidinyl.

Preferred heteroatoms are N and S, especially N. In general, attachmentof heterocyclic rings to other groups is via carbon atoms.

Examples of values for R⁸ in Formula (2) are side chains of lipophilicamino acids including such as for example methionine, phenylglycine,phenylalanine, serine, leucine, isoleucine or valine. The Lconfiguration in the corresponding free amino acid is preferred.Examples of amino acid side chains are set out below.

Amino Acid Side Chain methionine —CH₂—CH₂—S—CH₃ phenylglycine Phphenylalanine —CH₂-Ph thienylalanine —CH₂-thien-2-yl serine —CH₂OH or aC₁₋₄alkyl (preferably methyl) ether thereof. Leucine —CH₂—CHMe₂homoserine —CH₂—CH₂—OH or a C₁₋₄alkyl (preferably methyl) ether thereofN-acetyl-lysine —CH₂—CH₂—CH₂—CH₂—NH—CO—CH₃

The lactone in Formula (3) can be formed from a group of Formula (2)when R⁹ is OH to give a carboxyl and R⁸ is —CH₂—CH₂—OH where R⁸ and R⁹together lose a water molecule to form part of a dihydrofuran-2-oneheterocyclic ring.

Preferably, phenyl and heteroaryl rings in R³, R⁵, R⁶, R¹¹ and R¹⁵(including R¹⁷ and R¹⁸) are independently optionally substituted on ringcarbon atoms by up to two substituents selected from C₁₋₄alkyl, halogen,hydroxy, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkanoylamino, cyano,carboxy, C₁₋₄alkylsufanyl, C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl,C₁₋₄alkanesulphonamido, carbamoyl, N—(C₁₋₄alkyl)carbomoyl,N,N-(diC₁₋₄alkyl)carbamoyl and on ring NH groups (replacing hydrogen) byC₁₋₄alkyl or C₁₋₄alkanoyl.

Preferably R¹² and R¹³ are independently hydrogen or methyl.

Most preferably R¹² and R¹³ are hydrogen. Preferably R⁶ is hydrogen,C₁₋₄alkyl, hydroxyC₁₋₄alkyl, aminoC₁₋₄alkyl, fluoroC₁₋₄alkyl,difluoroC₁₋₄alkyl, C₁₋₄alkoxy or C₁₋₄alkoxyC₁₋₄alkyl.

More preferably R⁶ is hydrogen, methyl, fluoromethyl, difluoromethyl,methoxy or methoxymethyl.

Most preferably R⁶ is hydrogen or methyl.

Preferably m is 0 or 1.

Preferably R⁵ is hydrogen or methyl. More preferably R⁵ is hydrogen.

In a particular aspect Ar¹ is 1 -methylimidazol-5-yl.

Preferably Ar² is phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl,thienyl, thiazolyl, or oxazolyl, the ring being substituted on ringcarbon atoms by R² and —(CH₂)_(n)R³. Most preferred is where Ar² isphenyl, pyridinyl or thienyl, the ring being substituted on ring carbonatoms by R² and —(H₂)_(n)R³.

More preferably Ar² is phenyl, pyridinyl or thienyl, the ring beingsubstituted on ring carbon atoms by R² and —(CH₂)_(n)R³.

Yet more preferably Ar² is phenyl or pyridyl, the ring being substitutedon ring carbon atoms by R² and —(CH₂)_(n)R³.

Most preferably Ar² is phenyl, the ring being substituted on ring carbonatoms by R² and —(CH₂)_(n)R³.

Preferably, when n is 0, Ar² is substituted by R² in the 4-position and—(CH₂)_(n)R³ in the 3- or 5-position and when n is 1 or 2, Ar² issubstituted by R² in the 3- or 5-position and —(CH₂)_(n)R² in the4-position. The positions indicated are relative to the point ofattachment of Ar² to Ar¹C(R¹²)R¹³CH═CH—.

Preferably n is 0 or 2. In a particular aspect n is 0.

R² is preferably a group of formula:

R⁷ is preferably hydrogen or methyl, especially hydrogen. In R⁸, q ispreferably 1-4, more preferably 1 or 2, especially 2.

Within R⁸, R¹⁰ is preferably C₁₋₄alkylsulfanyl, C₁₋₄alkylsulfinyl,C₁₋₄alkylsulfonyl, hydroxy or C₁₋₄alkoxy. More preferably R¹⁰ ismethylsulfanyl or methylsulfonyl.

R⁹ is preferably hydroxy, C₁₋₄alkoxy, C₃₋₉cycloalkyloxy, heterocyclyloxyor heterocyclylC₁₋₄alkoxy. More preferably R⁹ is hydroxy, methoxy,propoxy, butoxy, tert-butoxy, cyclopentyloxy, piperidin-4-yloxy ormorpholinoC₁₋₄alkyl. Most preferably, R⁹ is methoxy, prop-2-oxy,n-butoxy, tert-butoxy or cyclopentyloxy.

Preferably R¹¹ in R⁹ is phenyl.

Preferred substituents for NH groups in heterocyclic groups in R⁹include methyl, ethyl, acetyl, propionyl, fluoromethyl, difluoromethyland trifluoromethyl.

More preferred substituents for NH groups in heterocyclic groups in R⁹include methyl and acetyl.

Preferred substituents for ring carbon atoms in phenyl or heteroarylgroups in R¹¹ include methyl, halo, C₁₋₄alkanoyl, nitro, cyano,C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl, carbamoyl, C₁₋₄alkylcarbamoyl anddiC₁₋₄alkylcarbamoyl.

Formula (4) is preferably a group of formula:

In R¹⁴, q is preferably 1-4, more preferably 1 or 2, especially 2.

Within R¹⁴, R¹⁴ is preferably C₁₋₄alkylsulfanyl, C₁₋₄alkylsulfinyl,C₁₋₄alkylsulfonyl, hydroxy or C₁₋₄alkoxy. More preferably R¹⁶ in R¹⁴ ismethylsulfanyl or methylsulfonyl. Preferably R¹⁷ in R¹⁵ is hydrogen orphenyl.

Most preferably R¹⁷ in R¹⁵ is hydrogen.

Preferably R¹⁸ in R¹⁵ is C₁₋₄alkyl, phenyl, phenylC₁₋₃alkyl, heteroaryl,heteroarylC₁₋₃alkyl or C₅₋₇cycloalkylC₁₋₃alkyl.

More preferably R¹⁸ in R¹⁵ is C₁₋₄alkyl, phenyl, phenylC₁₋₃alkyl orheteroaryl.

Most preferably R¹⁸ in R¹⁵ is C₁₋₄alkyl, phenyl or benzyl.

Preferably when R¹⁸ is C₁₋₄alkyl, it is optionally substituted by halo,cyano or C₂₋₆alkanoyloxy.

Preferably morpholinoC₁₋₄alkyl is morpholinomethyl,pyrrolidin-1-ylC₁₋₄alkyl is pyrrolidin-1-ylmethyl andpiperidin-1-ylC₁₋₄alkyl is piperidin-1-ylmethyl.

In one aspect R¹⁵ is morpholinomethyl.

More preferably R¹⁵ is hydroxymethyl, benzylcarbonyl,3-(pyridyl)propionyl or morpholinomethyl.

Most preferably R¹⁵ is hydroxymethyl or benzylcarbonyl. R¹⁴ is—(CH₂)_(q)R¹⁶ wherein q is 0-4 and R¹⁶ is C₁₋₄alkylsulfanyl,C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl, hydroxy or C₁₋₄alkoxy; or R¹⁵ ismorpholinomethyl, pyrrolidin-1-ylmethyl or piperidin-1-ylmethyl; or R¹⁵is of the formula —CH₂OR¹⁷ wherein R¹⁷ is hydrogen or phenyl; or R¹⁵ isof the formula —COR¹⁸ or —CH₂COR¹⁸ wherein R¹⁸ is C₁₋₄alkyl, phenyl,phenylC₁₋₃alkyl, heteroaryl, heteroarylC₁₋₃alkyl orC₅₋₇cycloalkylC₁₋₃alkyl; Preferably R³ is phenyl, pyridyl or thiazolyl.

Most preferably R³ is phenyl.

Preferred substituents for ring carbon atoms in R³ include C₁₋₄alkyl,halo, trifluoromethyl, C₁₋₄alkoxy, nitro, cyano and C₁₋₄alkoxyC₁₋₄alkyl.

More preferred substituents for ring carbon atoms in R³ include methyl,fluoro, chloro, trifluoromethyl, methoxy, nitro, cyano andmethoxymethyl.

When R³ is phenyl it is preferably mono-substituted by fluoro, chloro orcyano or di-substituted by fluoro and triflouromethyl, chloro andtrifluoromethyl, fluoro and fluoro or chloro and chloro.

A preferred substituent for a ring NH group in a heteroaryl group in R³is C₁₋₄alkyl, particularly methyl.

When R³ is phenyl it is preferably substituted in the 4-position, andwhen di-substituted it is preferably substituted in the 2- and4-positions.

Preferably n is 0 or 2.

Preferably R⁷ is hydrogen.

Preferably R⁸ is —(CH₂)—R¹⁰ is C₁₋₄alkylsulfonyl or C₁₋₄alkylsulfonyl.

Preferably R⁹ is hydroxy, C₁₋₄alkoxy, C₃₋₉cycloalkyloxy, heterocyclyloxyor heterocyclylC₁₋₄alkoxy.

A preferred compound of the invention is a compound of the Formula (I)wherein:

Ar¹ is of the formula (A), (B) or (C);

R⁵ is hydrogen or methyl;

R⁶ is hydrogen, C₁₋₄alkyl, fluoroC₁₋₄alkyl, difluoroC₁₋₄alkyl,C₁₋₄alkoxy or C₁₋₄alkoxyC₁₋₄alkyl;

m is 0 or 1;

R¹² and R¹³ are independently hydrogen or methyl;

Ar² is phenyl or pyridyl, the ring being substituted on ring carbonatoms by R² and —(CH₂)_(n)R¹⁰ and wherein Ar² is attached toAr¹C(R¹²)R¹³CH═CH— by a ring carbon atom; and

n is 0, 1 or 2;

R² is of the formula (2) wherein R⁷ is hydrogen or methyl;

R⁵ is —(CH₂)_(q)R¹⁰ wherein q is 0-4 and R¹⁰ is C₁₋₄alkylsulfanyl,C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl, hydroxy or C₁₋₄alkoxy;

R⁹ is hydroxy, C₁₋₄alkoxy, C₃₋₉cycloalkyloxy, heterocycloxy orheterocyclylC₁₋₄alkoxy;

or R² is of the formula (3);

R³ is phenyl, pyridyl or thiazolyl; and phenyl, heteroaryl andheterocyclyl rings in R³ and R⁹ are independently optionally substitutedon ring carbon atoms by one or two substituents selected from C₁₋₄alkyl,halo, C₁₋₄alkoxy, C₁₋₄alkanoyl, nitro, cyano, C₁₋₄alkylsulfinyl,C₁₋₄alkylsulfonyl, carbamoyl, C₁₋₄alkylcarbamoyl anddiC₁₋₄alkylcarbamoyl; and optionally substituted on ring NH groups byC₁₋₄alkyl, C₁₋₄alkanoyl, fluoromethyl, difluoromethyl ortrifluoromethyl;

or a pharmaceutically-acceptable salt, prodrug or solvate thereof.

A more preferred compound of the invention is a compound of the formula(I) wherein:

Ar¹ is of the formula (A), (B) or (C);

R⁵ is hydrogen or methyl;

R⁶ is hydrogen, methyl, fluoromethyl, difluoromethyl, methoxy ormethoxymethyl;

m is 0 or 1;

R¹² and R¹³ are independently hydrogen or methyl;

Ar² is phenyl or pyridyl; the ring being substituted on ring carbonatoms by R² and —(CH₂)_(n)R³ and wherein Ar² is attached toAr¹C(R¹²)R¹³CH═CH— by a ring carbon atom; and n is 0, 1 or 2;

R² is of formula (2) wherein R⁷ is hydrogen or methyl;

R⁸ is (CH₂)_(q)R¹⁰ wherein q is 1 or 2, and

R¹⁰ is methylsulfanyl or methylsulfonyl;

R⁹ is hydroxy, methoxy, prop-2-oxy, butoxy, tert-butoxy, cyclopentyloxy,piperidin -4 -yloxy, or morpholinoC₁₋₄alkyl; or R² is of the formula(3);

R³ is phenyl optionally substituted by one or two substituents selectedfrom C₁₋₄alkyl, halo, C₁₋₄alkoxy, nitro, cyano, C₁₋₄alkoxyC₁₋₄alkyl andtrifluoromethyl;

or a pharmaceutically-acceptable salt, prodrug or solvate thereof.

An even more preferred compound of the invention is a compound of theformula (I) wherein:

Ar¹ is of the formula (A), (B) or (C);

R⁵ is hydrogen or methyl;

R⁶ is hydrogen or methyl;

m is 0 or 1;

R¹¹ and R¹² are hydrogen;

Ar² is phenyl; the ring being substituted on ring carbon atoms by R² and—(CH₂)_(n)R³ and wherein

Ar² is attached to Ar¹(R¹²)R¹³CH═CH— by a ring carbon atom;

and n is 0, 1 or 2;

R² is of the Formula (2) wherein R⁷ is hydrogen;

R⁸ is —(CH₂)₈R¹⁰ wherein q is 2 and within Formula (2)

R¹⁰ is methylsulfanyl or methylsulfonyl;

R⁹ is hydroxy, methoxy, prop-2-oxy, butoxy, tert-butoxy, cyclopentyloxy,piperidin-4-yloxy, or 2-morpholinoprop-2-yl; or within Formula (4)

R¹⁵ is of the fomula —CH₂OR¹⁷ wherein R¹⁷ is hydrogen; or R¹⁵ is of theformula —COR¹⁸ or —CH₂COR¹⁵ wherein R¹⁸ is C₁₋₄alkyl, phenyl,phenylC₁₋₃alkyl or heteroaryl; or

R¹⁵ is morpholinomethyl, pyrrolidin-1-ylmethyl or piperidin-1-ylmethyl;

R³ is phenyl optionally substituted by fluoro, chloro, cyano ortrifluoromethyl;

or a pharmaceutically-acceptable salt, prodrug or solvate thereof.

Preferably Ar¹C(R¹²)R¹³— and Ar² are on opposite sides of the doublebond (this gives the E isomeric configuration).

Particular compounds of the present invention include those compoundsspecifically described in the Examples; or a pharmaceutically-acceptablesalt, prodrug or solvate thereof.

Compounds of Formula (1) may form salts which are within the ambit ofthe invention. Pharmaceutically acceptable salts are preferred althoughother salts may be useful in, for example, isolating or purifyingcompounds.

When the compound contains a basic moiety it may formpharmaceutically-acceptable salts with a variety of inorganic or organicacids, for example hydrochloric, hydrobromic, sulphuric, phosphoric,trifluoroacetic, citric or maleic acid. A suitablepharmaceutically-acceptable salt of the invention when the compoundcontains an acidic moiety is an alkali metal salt, for example a sodiumor potassium salt, an alkaline earth metal salt, for example a calciumor magnesium salt, an ammonium salt or a salt with an organic base whichaffords a pharmaceutically-acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Solvates, for example hydrates, are also within the ambit of theinvention and may be prepared by generally known methods.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285(1988); and

e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

Examples of pro-drugs include in vivo hydrolysable esters of a compoundof the Formula I. Suitable pharmaceutically-acceptable esters forcarboxy include C₁₋₄alkyl esters, C₅₋₈cycloalkyl esters, cyclic amineesters, C₁₋₆alkoxymethyl esters for example methoxymethyl,C₁₋₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethylwherein alkyl, cycloalkyl and cyclicamino groups are optionallysubstituted by, for example, phenyl, heterocyclcyl, alkyl, amino,alkylamino, dialkylamino, hydroxy, alkoxy, aryloxy or benzyloxy, and maybe formed at any carboxy group in the compounds of this invention.

According to another aspect of the invention there is provided apharmaceutical composition comprising a compound as defined in Formula(1) or an individual compound listed above together with apharmaceutically-acceptable diluent or carrier. A preferredpharmaceutical composition is in the form of a tablet.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedure well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30μ or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on Formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula (1) will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. As mentioned above, compounds of the Formula (1) are useful intreating diseases or medical conditions which are due alone or in partto the effects of farnesylation of ras.

In using a compound of the Formula (1) for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used. Oral administration is howeverpreferred.

Compounds of this invention may be useful in combination with knownanti-cancer and cytotoxic agents. If formulated as a fixed dose suchcombination products employ the compounds of this invention within thedosage range described herein and the other pharmaceutically activeagent within its approved dosage range. Sequential use is contemplatedwhen a combination formulation is inappropriate. According to anotheraspect of the invention there is provided a compound of Formula (1) or apharmaceutically-acceptable salt thereof, for use as a medicament.

According to another aspect of the invention there is provided acompound of Formula (1) or a pharmaceutically-acceptable salt thereof,for use in preparation of a medicament for treatment of a diseasemediated through farnesylation of ras.

According to another aspect of the present invention there is provided amethod of treating ras mediated diseases, especially cancer, byadministering an effective amount of a compound of Formula (1) or apharmaceutically-acceptable salt thereof, to a mammal in need of suchtreatment.

Diseases or medical conditions may be mediated alone or in part byfarnesylated ras. A particular disease of interest is cancer. Specificcancers of interest include:

carcinoma, including that of the bladder, breast, colon, kidney, liver,lung, ovary, pancreas, stomach, cervix, thyroid and skin;

hematopoietic tumors of lymphoid lineage, including acute lymphocyticleukemia, B-cell lymphoma and Burketts lymphoma;

hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias and promyelocytic leukemia;

tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma; and

other tumors, including melanoma, seminoma, tetratocarcinoma,neuroblastoma and glioma.

The compounds of Formula (1) are especially useful in treatment oftumors having a high incidence of ras mutation, such as colon, lung, andpancreatic tumors. By the administration of a composition having one (ora combination) of the compounds of this invention, development of tumorsin a mammalian host is reduced.

Compounds of Formula (1) may also be useful in the treatment of diseasesother than cancer that may be associated with signal transductionpathways operating through Ras, e.g., neuro-fibromatosis.

Compounds of Formula (1) may also be useful in the treatment of diseasesassociated with CAAX-containing proteins other than Ras (e.g., nuclearlamins and transducin) that are also post-translationally modified bythe enzyme farnesyl protein transferase.

Although the compounds of the Formula (1) are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects ofactivation of ras by farnesylation. Thus, they are useful aspharmacological standards for use in the development of new biologicaltests and in the search for new pharmacological agents.

In another aspect the present invention provides a process for preparinga compound of the Formula (1) or a pharmaceutically-acceptable saltprodrug or solvate thereof which process comprises:

deprotecting a compound of the formula (5)

wherein Ar^(1′) is Ar¹ or protected Ar¹ and Ar^(2′) is Ar² or protectedAr² and R¹² and R¹³ are as hereinabove defined; wherein at least oneprotecting group is present; and thereafter if necessary:

(i) forming a pharmaceutically-acceptable salt,

(ii) forming a prodrug,

(iii) forming a solvate.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question, and may beintroduced by conventional methods.

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower” signifies that the group to which it isapplied preferably has 1-4 carbon atoms. It will be understood thatthese examples are not exhaustive. Where specific examples of methodsfor the removal of protecting groups are given below these are similarlynot exhaustive. The use of protecting groups and methods of deprotectionnot specifically mentioned is of course within the scope of theinvention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or araliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).

Examples of carboxy protecting groups include straight or branched chainC₁₋₁₂alkyl groups (for example isopropyl, t-butyl); lower alkoxy loweralkyl groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl);lower aliphatic acyloxy lower alkyl groups, (for example acetoxymethyl,propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); loweralkoxycarbonyloxy lower alkyl groups (for example1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); phenyl lower alkylgroups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups(for example trimethylsilyl and t-butyldimethylsilyl); tri(loweralkyl)silyl lower alkyl groups (for example trimethylsilylethyl); andC₁₋₆alkenyl groups (for example allyl and vinylethyl).

Methods particularly appropriate for the removal of carboxy protectinggroups include for example acid-, base-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxy protecting groups include lower alkyl groups (forexample t-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample t-butoxycarbonyl); lower alkenyloxycarbonyl groups (for exampleallyloxycarbonyl); phenyl lower alkoxycarbonyl groups (for examplebenzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkylsilyl (for example trimethylsilyl, t-butyldimethylsilyl) and phenyllower alkyl (for example benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (forexample benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl andfurylmethyl groups; lower alkoxycarbonyl (for example t-butoxycarbonyl);lower alkenyloxycarbonyl (for example allyloxycarbonyl); phenyl loweralkoxycarbonyl groups (for example benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl andt-butyldimethylsilyl); alkylidene (for example methylidene); benzylideneand substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenationand for groups such as o-nitrobenzyloxycarbonyl, photolytically.

The reader is referred to Advanced Organic Chemistry, 4th Edition, byJerry March, published by John Wiley & Sons 1992, for general guidanceon reaction conditions and reagents. The reader is referred toProtective Groups in Organic Synthesis, 2nd Edition, by Green et al.,published by John Wiley & Sons for general guidance on protectinggroups.

Compounds of the formula (1) and (5) can be formed by:

(i) reacting a compound of the formula (6) with a compound of theformula (7):

or (ii) converting one value of R⁹ in R² into another value of R⁹;

or (iii), where the compound of formula (I) includes alternatives offormula (2) and (3), reacting a compound in which R² in Ar^(2′) iscarboxy with a compound of the formula (8):

or (iv), where the compound of formula (I) includes alternative offormula (4), reacting a compound in which R² in Ar² is carboxy with acompound of formula (8a).

or (v) when Ar^(1′) is of the formula (B) or (C) (optionally protected),reacting a compound of the formula (9) or (9a) with a compound of theformula (10):

 wherein p, Ar^(1′), Ar^(2′), Ar^(3′) R⁷ and R⁸ are as hereinabovedefined, R²¹ is R⁹ or protected R⁹, L¹ and L² are leaving groups and P′is an amino-protecting group or R⁵ providing it is not hydrogen; andthereafter if necessary:

(i) removing any protecting groups;

(ii) forming a pharmaceutically-acceptable salt, prodrug or solvatethereof.

The reaction between compounds of the formula (6) and (7) isconveniently carried out under conditions know for the Wittig reaction.

Suitable Wittig reaction conditions include using a polar aproticorganic solvent such as THF or methylene chloride in the presence of acrown ether and an alkali metal carbonate, such as potassium carbonate,preferably at −10° C. to ambient temperature. C18 HPLC may be used toseparate E and Z isomers if desired.

The Wittig reaction can be used to prepare a compound wherein R² inAr^(2′) is an alkoxycarbonyl group which may be hydrolysed to a carboxygroup. If Ar^(1′) is of the formula (A), and the latter route is chosenand basic conditions are used, the E and Z isomers produced by theWittig reaction are generally not separated if the E isomer is wanted,because the base-hydrolysis step causes isomerisation of the Z isomer tothe E isomer.

A compound of the formula (6) is generally prepared by reducing thecorresponding ester to the aldehyde. A suitable reducing agent is forexample DIBAL which is used in an inert non-polar solvent such asdiethyl ether at low temperature, for example in the range −78° C. to 0°C. Other suitable reducing agents are known in the art.

Alternatively, the ester could be reduced to the corresponding alcoholwith a reducing agent such as lithium aluminium hydride or sodiumborohydride and the alcohol oxidised to the aldehyde with an oxidisingagent such as pyridinium chlorochromate.

The ester used to form a compound of the formula (6) can be prepared byintroducing Are into a compound of the formula L⁴CH₂COOR, wherein L⁴ isleaving group such as bromo, in the presence of a base such as sodiumhydride, sodium hydroxide or potassium carbonate.

A compound of the formula (7) may be known in the art (for example seeInternational Patent Application publication no. WO 98/32741) or may beprepared by reacting a compound of the formula Ar^(2′)CH₂Br withtriphenylphosphine.

A compound of the formula Ar^(2′)CH₂Br may be formed by brominating acompound of the formula Ar^(2′)CH₃ with a suitable brominating agentsuch as N-bromosuccinimide.

A compound of the formula Ar^(2′)CH₃ wherein the Ar^(2′) group issubstituted by R² and —(CH₂)_(n)R³ group may be prepared from a compoundof the formula Ar^(2′)CH₃ wherein the Ar² group is substituted by—(CH₂)_(n)R³ and —COOH′ using methods described above for the conversionof —COOH to R². This latter Ar²′CH₃ compound could be prepared from acompound of the formula Ar^(2′)CH₃ wherein the Ar^(2′) group issubstituted by a protected carboxy group (—COOP²) and a leaving group(L³). When n is 0, the CH₃Ar^(2′)(—COOP₂)—L³ compound is convenientlyreacted with aryl (or heteroaryl) boronic acid in the presence of apalladium catalyst such as palladium tetrakis (triphenylphosphine)palladium (0) under conditions known for the Suzuki reaction (Synth.Commun. 11, 513 (1981)). An aprotic organic solvent such as dimethylether (DME), toluene, dimethylsulphoxide (DMSO) or THF is generally usedand a base such as sodium bicarbonate, sodium carbonate and sometimessodium hydroxide. A fluoride such as caesium fluoride could be usedinstead of the base (J. Org. Chem. 1994, 59, 6095-6097). Preferably L³is bromo or triflate.

When n is 1, the CH₃Ar^(2′)(—COOP²)—L³ compound wherein L³ is bromo orchloro, is conveniently reacted with a benzyl (or heteroarylmethyl) zincchloride or a benzyl (or heteroarylmethyl)-magnesium bromide in thepresence of a nickel or palladium catalyst, such asbis(triphenylphosphine)palladium (II) chloride or Pd₂(dba)₃, in an inertorganic solvent such as tetrahydrofuran (THF). For example see theconditions used for the ‘Negishi’ reaction (J. Org. Chem. 42 (10),1821-1822, 1977).

When n is 2, the CH₃Ar^(2′)(—COOP²)—L³ compound is conveniently reactedwith a styrene under conditions known for the Heck reaction. Brieflythis involves an inorganic or organic base such as triethylamine, apalladium catalyst such as bis (o-tolylphosphine)palladium (II) chloridein water. (Acc. Chem. Res. 12, 146-151 (1979), J. Organometallic Chem.486, 259-262 (1995)).

The resulting alkene can then be reduced using standard methods known inthe art, for example, catalytic hydrogenation.

Alternatively the alkyne could be formed by reacting aCH₃Ar^(2′)(—COOP₂)—L³ compound, wherein L³ is triflate or bromo, with aphenyl acetylene in the presence of an organic base such astriethylamine and a palladium catalyst such as palladium tetrakis(triphenylphosphine). For example see the conditions used for theSonogashira reaction (J. Org. Chem. 1993,58, 6614-6619).

The resultant alkyne can be reduced using standard methods known in theart, for example, catalytic hydrogenation.

The carboxy-protecting group may then be removed.

A compound of the formula (1) in which R⁹ in R² is alkoxy canconveniently be hydrolysed to another compound of the formula (1) inwhich R⁹ is hydroxy using standard methods known in the art. Forexample, the alkoxy group could be subjected to acid or base hydrolysiswith, for example, in the case of base hydrolysis, aqueous sodiumhydroxide solution in an organic solvent such as an alcohol in atemperature range of ambient temperature to 60° C. When R⁹ is a hydroxygroup the carboxy group in a compound of the formula (1) can beconverted to an acylsulphonamide by reacting the carboxy group with theappropriate sulphonamido group in the presence of an organic base suchas triethylamine or dimethylaminopyridine, in an inert organic solventsuch as dimethylformamide (DMF), in temperature range of −20° C. toambient temperature.

The reaction between a compound in which R² in Ar^(2′) is carboxy and acompound of the formula (8) and (8a) is generally carried out in thepresence of a reagent that converts the carboxy group into a reactiveester, for example a carbodiimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) orpentafluorophenyl, and in the presence of an organic base such asN-methylmorpholine. The reaction is usually carried out in thetemperature range of −20° C. to ambient temperature. The reagents,1-hydroxybenzotriazole and dimethylaminopyridine (DMAP), are often addedto assist the reaction (see Chem. Ber. 103, 788, 2024 (1970), J. Am.Chem. Soc. 93, 6318 (1971), Helv. Chim. Acta. 56, 717, (1973)). Suitablesolvents include DMF and dichloromethane.

For examples of suitable conditions for amide bond forming reactions seeInternational Patent Application No. WO 98/07692.

A compound of the formula (1) in which R² in Ar^(2′) is carboxy can beprepared by reacting a compound of the formula (6) with a compound ofthe formula (7), or a compound of the formula (9) or (9a) with acompound of the formula (10) wherein R² in Ar^(2′) is protected carboxyand subsequently removing the carboxy-protecting group.

A compound of the formula (8a) wherein R²² is of the formula —COR¹⁸ canbe formed via the intermediate NH₂CH(R²¹)CON(OMe)Me which itself isformed by reacting together NH₂CH(R²¹)COOH withN,O-dimethylhydroxylamine under standard amide bond forming conditions.A compound of the formula NH₂CH(R²¹)CON(OMe)Me is then convenientlyreacted with a Gringard reagent (such as PhCH₂MgCl) to form a compoundof the formula (8).

Alternatively, when R¹⁸ contains an alkyl chain linked to the carbonylgroup, a compound of the formula NH₂CH(R²¹)CON(OMe)Me can be convertedto the corresponding dimethylphosphono compound (NH₂CH(R²¹)COP(O)(OMe)₂)by reacting the former compound with dimethylmethylphosphonate in thepresence of a strong base such as n-butyl lithium. A compound of theformula (8) can be formed by reacting the dimethylphosphono compoundwith the appropriate aldehyde or ketone under conditions known for theWittig or Emmons-Horner reactions.

A compound of the formula (8) wherein R²² is morpholinomethyl,pyrrolidin-1-ylmethyl or piperidin-1-ylmethyl is conveniently preparedby reacting NH₂CH(R²¹)COOH with the appropriate heterocyclic ring understandard amide bond forming conditions to form a compound of the formula(8), wherein R¹⁵ is heterocyclylcarbonyl, and subsequently reducing thecarbonyl group to a methyl group with a reducing agent such as lithiumaluminium hydride.

A compound of the formula NH₂CH(R²¹)COOH can be extended by one carbonlength to produce a compound of the formula NH₂CH(R²¹)CH₂COOH using theArndt-Eistert homologation method. For example by converting the carboxygroup to an acid chloride, converting the latter to the diazoketone andhydrolysing this to the carboxylic acid. This homologation method couldbe used to produce subsequent homologues. A compound of the formulaNH₂CH(R²¹)CH₂COOH and homologues may be used to prepare a compound ofthe formula NH₂CH(R²¹)R²² wherein R²² is of the formula —CH₂COR¹⁵,morpholino C₁₋₄alkyl, pyrrolidin-1-ylC₁₋₄alkyl orpiperidin-1-ylC₁₋₄alkyl.

An anion of the formula (9) is conveniently formed with a strong base,such as n-butyl lithium. This generally forms an anion at the 2-positionof the imidazole compound. The anion formation is generally carried outat low temperature e.g. −78° C., in an inert or organic solvent such asdiethyl ether.

The anion (usually the lithium anion) of a compound of the formula (9)is normally converted to an organozinc reagent in the presence oflithium chloride, zinc iodide and copper (I) cyanide and this complex isreacted with a compound of the formula (10) in an inert organic solventsuch as tetrahydrofuran in a temperature range of −78° C. to ambienttemperature (see the review of organozinc reagents by Paul Knochel andRobert D Singer in Chem. Rev. 1993, 93, 2117-2188).

The anion of a compound of the formula (9a) is conveniently formed as aGrignard reagent by reacting the latter compound with an alkyl magnesiumbromide in an ether at low temperature. The resulting Grignard reagentis typically reacted with a compound of the formula (10) in the presenceof copper (I) cyanide and lithium chloride, allowing the temperature torise from −78° C. to ambient temperature. Preferably L¹ in the compoundof the formula (9a) is halo, for example iodo or bromo.

Preferably L² in the compound of the formula (10) is halo, for examplebromo.

A compound of the formula (10) may be prepared by brominating thecorresponding hydroxy compound with a brominating agent such astetrabromomethane/triphenylphosphine in a suitable solvent such asdichloromethane. The hydroxy compound is typically prepared by reactinga compound of the formula (7) and glycoaldehyde under conditions knownfor the Wittig reaction such as those described above for the reactionbetween compounds of the formulae (6) and (7).

The order in which the various groups are introduced can be varieddepending upon the nature of the desired final product. In general, thepreferred last step is the formation or modification of R² in Ar^(2′).For example, when R⁹ is hydroxy, the hydrolysis of the compound whereinR⁹ is alkoxy, or when R⁹ is other than hydroxy, the conversion of acarboxy group to R² using the amide bond-forming conditions describedabove.

When Ar^(1′) of the formula (A), it is preferable to form the alkenewhich contains a protected carboxy group later to be converted to R², byreacting together compounds of the formulae (6) and (7).

When Ar^(2′) is of the formula (B) or (C) the alkene which contains aprotected carboxy group later to be converted to R², is preferablyformed by reacting together a compound of the formula Ar^(2′)CH₂P⁺Ph₃Br(wherein Ar^(2′) is substituted by —COOP² in place of R²) andglycoaldehyde, converting the resultant hydroxy compound to a compoundof the formula (9) (wherein Ar^(2′) is substituted by —COOP² in place ofR²) and reacting the latter compound with a compound of the formula (8)or (8a).

Optionally substituents in a compound of the formula (1) and (5) orintermediates in their preparation may be converted into other optionalsubstituents. For example an alkylthio group may be oxidised to analkylsulphinyl or alkysulphonyl group, a nitro group reduced to an aminogroup, a hydroxy group alkylated to a methoxy group, or a bromo groupconverted to an alkylthio group.

Various substituents may be introduced into compounds of the formulae(1) and (5) and intermediates in this preparation, when appropriate,using standard methods known in the art. For example, an acyl group oralkyl group may be introduced into an activated benzene ring usingFriedel-Crafts reactions, a formyl group by formylation with titaniumtetrachloride and dichloromethyl ethyl ester, a nitro group by nitrationwith concentrated nitric acid concentrated sulphuric acid andbromination with bromine or tetra(n-butyl)ammonium tribromide.

It will be appreciated that, in certain steps in the reaction sequenceto compounds of the formula (1), it will be necessary to protect certainfunctional groups in intermediates in order to prevent side reactions.Deprotection may be carried out at a convenient stage in the reactionsequence once protection is no longer required.

Biological activity was tested as follows:

(i) In-vitro Assay

The following stock solutions were used and the assays were conducted in96 well plates: TRIS Buffer (500 mM TRIS, 5 mM MgCl₂.6H₂O, pH=8.0);Farnesyl pyrophosphate (6.4 mg/ml); Aprotinin (1.9 mg/ml); Ki-ras (0.5mg/ml, stored at −80° C.); Acid ethanol (850 ml absolute ethanol+150 mlconcentrated HCl).

Farnesyl protein transferase (FPT) was partially purified from humanplacenta by ammonium sulphate fractionation followed by a singleQ-Sepharose™ (Pharmacia, Inc) anion exchange chromatography essentiallyas described by Ray and Lopez-Belmonte (Ray K P and Lopez-Belmonte J(1992) Biochemical Society Transactions 20 494-497). The substrate forFPT was Kras (CVIM C-terminal sequence). The cDNA for oncogenic val 12variant of human c-Ki-ras-2 4B was obtained from the plasmid pSW11-1(ATCC). This was then subcloned into the polylinker of a suitableexpression vector e.g. pIC147. The Kras was obtained after expression inthe E. coli strain, BL21. The expression and purification of c-KI-ras-24B and the val12 variant in E. coli has also been reported by Lowe et al(Lowe P N et al. J. Biol. Chem. (1991) 266 1672-1678). The farnesylprotein transferase enzyme preparation was stored at −80° C.

The farnesyl transferase solution for the assay contained the following:dithiothreitol (DTT)(0.6 ml of 7.7 mg/ml), TRIS buffer (0.6 ml),aprotinin (0.48 ml), distilled water (1.2 ml), farnesyl transferase (0.6ml of the crude enzyme preparation prepared as described above), zincchloride (12 μl of 5 mM). This was left at ambienttemperature for 30minutes. After this incubation 60 μl Ki-ras solution was added and thewhole left to incubate for a further 60 minutes prior to use in theassay.

Assays were performed in 96 well plates as follows: 10 μl of testcompound solution was added to each well. Then 30 μl farnesyltransferase solution (above) was added and the reaction started byaddition of 10 μl radiolabelled farnesyl pyrophosphate solution. After20 minutes at 37° C. the reaction was stopped with 100 μl acid ethanol(as described in Pompliano D L et al (1992) 31 3800-3807). The plate wasthen kept for 1 hour at 4° C. Precipitated protein was then collectedonto glass fibre filter mats (B) using a Tomtec™ cell harvester andtritiated label was measured in a Wallac™ 1204 Betaplate scintillationcounter. Test compounds were added at appropriate concentrations in DMSO(3% final concentration in test and vehicle control).

(ii) Intracellular Farnesylation Assay

HER313A cells (Grand et al, 1987 Oncogene 3, 305-314) were routinelycultured in Dulbecos Modified Essential Medium (DMEM) plus 10% foetalcalf serum (FCS). For the assay HER313A cells were seeded at 200,000cells/well in a volume of 2.5 ml in a 6 well tissue culture plate. Afteran overnight incubation at 37° C. in 10% CO₂ the medium was removed andreplaced with methionine-free minimal essential medium (MEM) and thecells incubated as above for 2 hours. After this time the medium wasremoved and replaced by methionine-free MEM (1 ml) and test compound(1-3 μl). The plates were then incubated for a further 2 hours asdescribed above and then 30 μCi of ³⁵S-methionine added to each well.The plate was then incubated overnight as described above. The mediumwas then removed and the cells were lysed with lysis buffer (1 ml)(composed of 1000 ml phosphate buffered saline, 10 ml trition X-100, 5 gsodium deoxycholate, 1 g sodium dodecylsulphate) containing aprotinin(10 μl/ml), the plate scrapped and then left for 10 minutes at 4° C. Thelysate was then clarified by centrifugation. To 0.8 ml of the clarifiedlysate 80 μl of Y13-259 pan-Ras antibody (isolated from thehybridoma—American Tissue Culture Collection Accession Number CRL-1742)(final concentration approximately 1 μ/ml, the exact workingconcentration was optimised for each batch of antibody isolated) andprotein G beads (30 μof 0.5 μg/ml) were added and the mixture incubatedovernight with constant agitation. The pellet was then collected bycentrifugation, washed and separated by SDS PAGE using a 15% gel.Radioactive bands were detected using a phosphorimager system.

(iii) Morphology and Proliferation Assay

MIA PaCa 2 cells (American Tissue Culture Collection Accession Number:CRL-1420) were routinely cultured in Dulbecos Modified Essential Medium(DMEM) plus 10% FCS in a 162 cm² tissue culture flask. For the assay thecells were seeded at 16,000 cells/well, in 12 well plates, in DMEMcontaining 5% charcoal dextran treated stripped FCS (1 ml) (obtainedfrom Pierce and Warriner). The cells were then incubated overnight at37° C. in 10% CO₂. Test compound was then added (10 μl) and the cellsincubated for 6 days as described above. On days 1, 2, 3 and 6 the cellswere monitored for signs of morphological change and toxicity. On day 6the cells were removed from the plate using trypsin/EDTA and counted todetermine the proliferation rate.

Although the pharmacological properties of the compounds of the Formula(1) vary with structural change as expected, in general compounds of theFormula (1) possess an IC₅₀ in test (i) above in the range, for example,0.00005 to 50 μM in test (i). Thus by way of example the compound ofExample 29 herein has an IC₅₀ of approximately 0.0004 μM in testunacceptable toxicity was observed at the effective dose for compoundstested of the present invention.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at ambient temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as nitrogenor argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany or high pressure liquidchromatography (HPLC) C18 reverse phase silica separation;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the end-products of the Formula (1) have satisfactory microanalysesand their structures were confirmed by nuclear magnetic resonance (NMR)and mass spectral techniques; chemical shift values were measured on thedelta scale; the following abbreviations have been used: s, singlet; d,doublet; t or tr, triplet; m, multiplet; br, broad;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, HPLC, infra-red (IR) or NMRanalysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the Formula (1) were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

DMAP 4-dimethylaminopyridine DMF dimethylformamide EDC1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HOBT1-hydroxybenzotriazole MCPBA m-chloroperoxybenzoic acid TFAtrifluoroacetic acid THF tetrahydrofuran

EXAMPLE 1(2S)-2-{4-[(E)-3-Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyricAcid

A solution of tert-butyl(2S)-2-{4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate(0.2 g; 0.4 mmol) in dichloromethane (2 ml) was treated at 0° C. withTFA (2 ml). The mixture was allowed to warm to ambient temperature andstirred for 1 hour. After evaporation of the solvent, the residue wastaken up with distilled water (5 ml); the pH was adjusted to 6 withNH₄OH and the solution was purified on reverse phase silica eluting withmethanol/ammonium carbonate buffer (2 g/l; pH 7) (40/60) to give thetitle compound after freeze-drying. Yield: 40%

¹H NMR (DMSO+CF₃COOD, 400 MHz) δ: 1.8-2 (2H, m); 2 (3H, s); 2.15-2.4(2H, m); 4.32 (1H, m); 5.05 (2H, m); 6.6-6.85 (2H, m); 7.20 (2H, m);7.4-7.6 (5H, m); 7.7-7.85 (2H, m); 9.21 (1H, s).

Anal. Calculated for C 60.90 H 5.58 N 8.88 S 6.77 C₂₄H₂₄N₃O₃SF 1.11 H₂OFound C 60.80 H 5.32 N 8.83 S 6.37

MS (ESI) m/z: 454 (MH⁺).

EXAMPLE 2 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazal-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

A solution of4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid(0.322 g; 1 mmol), EDC (0.230 g; 1.2 mmol), DMP (0.134 mg; 1.1 mmol),HOBT (162 mg; 1.2 mmol) and tert-butyl(2S)-2-amino-4-methylsulfanylbutanoate (L-methionine t-butyl ester) (0.3g; 1.5 mmol) in dichloromethane (20 ml) was stirred at ambienttemperature for 5 hours. The organic phase was washed with 5% sodiumhydrogen carbonate solution and evaporated to dryness; the residue waspurified by flash chromatography eluting with dichloromethane/ethanol(98/2) to give the title compound as a foam. Yield: 60%

¹H NMR (CDCl₃, 400 MHz) δ: 1.41 (9H, m); 1.7-2 (2H, m); 2 (3H, s); 2.18(2H, m); 4.54 (1H, m); 4.75 (2H, m); 6 (1H, d); 6.3-6.55 (2H, m); 6.96(1H, s); 7.05-7.70 (9H, m).

Anal. Calculated for C 65.99 H 6.33 N 8.24 S 6.29 C₂₈H₃₂FN₃O₃S Found C65.81 H 6.78 N 8.21 S 6.07

MS (ESI) m/z: 510 (MH⁺).

The starting material was prepared as follows:

A solution of DIBAL in hexane (440 ml) was added dropwise at −70° C.under argon atmosphere to a suspension of ethyl 2-(imidazol-1-yl)acetate(27.13 g; 0.176 mole) in ether (1.2 l). The mixture was stirred at −70°C. for 2 hours 30 minutes. Methanol (100 ml) and distilled water (8 ml)were then added at −70° C. and the mixture was allowed to warm toambient temperature and stirred for 2 hours. The resulting precipitatewas filtered, washed with dichloromethane/methanol (2×400 ml) and thefiltrate was evaporated and purified by flash chromatography elutingwith a gradient 10-25% methanol/dichloromethane to give2-(imidazol-1-yl)acetaldehyde which was isolated as the hemiacetal2-(imidazol-1-yl)-1-methoxyethanol. Yield: 68%

¹H NMR (CDCl₃, 400 MHz) δ: 3.48 (3H, s); 4.02 (2H, d); 6.9-7.5 (3H, m).

A solution of 2-(imidazol-1-yl)acetaldehyde (2.6 g; 0.018 mmol),3-(4-fluorophenyl)-4-methoxycarbonylbenzyl triphenylphosphonium bromide(5.4 g; 0.09 mmol), potassium carbonate (1.38 g; 0.01 mmol) and 18crown-6 (0.1 g; 0.37 mmol) in THF (150 ml) was stirred under argonatmosphere at ambient temperature overnight. After filtration of theinsoluble material and evaporation to dryness, the residue was purifiedby flash chromatography eluting with a mixture ofdichloromethane/ethanol (98/2) to give methyl4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate as amixture of E and Z isomers. Yield: 93%.

A solution of methyl4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (B and Zisomers) (1.9 g; 5.6 mmol) and 2N aqueous sodium hydroxide solution (8.5ml; 17 mmol) in methanol (100 ml) was refluxed for 9 hours. Afterevaporation and acidification with 12N HCl (1.5 ml), the resulting solidwas washed with distilled water and ether, taken up indichloromethane/methanol (99/1) to give4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid(E isomer) after evaporation as a foam. Yield: 89%

¹H NMR (DMSO+CF₃COOD, 400 MHz) δ: 5.06 (2H, d); 6.7-7.85 (2H, m);7.1-7.9 (9H, m); 9.22 (1H, s).

EXAMPLE 3 Methyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared using the same method as described forExample 2, but using the L-methionine methyl ester in place of theL-methionine tert-butyl ester. Yield: 83%

¹H NMR (CDCl₃, 400 MHz) δ: 1.75-2.05 (2H, m); 2.03 (3H, s); 2.15-2.25(2H, m); 3.68 (3H, s); 4.65-4.72 (1H, m); 4.74 (2H, m); 6 (1H, d);6.35-6.43 (1H, m); 6.52 (1H, d); 6.96 (1H, s); 7.1-7.7(9H, m).

Anal. Calculated for C 64.22 H 5.61 N 8.99 S 6.86 C₂₅H₂₆FN₃O₃S Found C63.87 H 5.73 N 8.80 S 6.58

MS (ESI) m/z: 4680 (MH⁺).

EXAMPLE 4 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfonylbutyrate

MCPBA (0.89 g; 3.1 mmol) was added to a solution of tert-butyl(2S)-2-{4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate(0.64 g; 1.25 mmol) in methylene chloride (15 ml) at 0° C. Afterstirring at ambient temperature for 2 hours, the solution was washedwith 1M Na₂S₂O₃, and 5% sodium hydrogen carbonate solution. The organiclayer was evaporated and the residue was purified by flashchromatography using a gradient of ethanol in dichloromethane (2%-4%) togive after evaporation of the appropriate fractions and trituration inether, the expected compound as a solid. Yield: 51%

M.P.: 100-104° C.; ¹H NMR (CDCl₃, 400 MHz) δ: 1.42 (9H, s); 1.9-2.4 (2H,m); 2.65-2.95 (2H, m); 2.84 (3H, s); 4.5 (1H, m); 4.74 (2H, d); 6.08(1H, d); 6.3-6.45 (2H, m); 6.96 (1H, s); 7.1-7.7 (9H, m).

Anal. Calculated for C 61.65 H 6.16 N 7.53 S 6.97 C₂₈H₃₂FN₃O₅S, 0.16Et₂O, 0.25 H₂O Found C 61.27 H 6.13 N 7.59 S 6.13

MS (ESI) m/z: 542 (MH⁺).

EXAMPLE 5(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfonylbutyricAcid

The title compound was prepared from Example 4 using similar methodologyto that of Example 1. Yield: 45%.

¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.9-2.25 (2H, m); 2.8-3.15 (2H, m);2.96 (3H, s); 4.35 (1H, m); 5.06 (2H, d); 6.6-6.8 (2H, m); 7.2 (2H, m);7.4-7.6 (5H, m); 7.74 (1H, d); 7.80 (1H, d); 9.21 (1H, s).

Anal. Calculated for C 56.04 H 5.33 N 8.17 S 6.25 C₂₄H₂₄FN₃O₅S, 1.6 H₂OFound C 55.76 H 4.88 N 8.16 S 6.34

MS (ESI) m/z: 486 (MH⁺).

EXAMPLE 6 2-Methyl-1-(morpholino)prop-2-yl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acidand the appropriate amine using a similar method to that of Example 2.Yield: 50%.

¹H NMR (CDCl₃, 400 MHz) δ: 1.42 (6H, m); 1.5-2.3 (4H, m); 2.04 (3H, s);2.4-2.6 (6H, m); 3.65 (4H, m); 4.54 (1H, m); 4.74 (2H, m); 5.98 (1H, d);6.3-6.6 (2H, m); 6.9-7.7 (10H, m).

Anal. Calculated for C 64.62 H 6.61 N 9.42 S 5.39 C₃₂H₃₉FN₄O₄S Found C64.39 H 6.86 N 9.55 S 6.09

MS (ESI) m/z: 595 (MH⁺).

EXAMPLE 7 Cyclopentyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluoropheny)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acidand the appropriate amine using a similar method to that of Example 2.Yield: 50%

¹H NMR (CDCl₃, 400 MHz) δ: 1.5-2.2 (12H, m); 2.03 (3H, s); 4.60 (1H, m);4.74 (2H, m); 5.12 (1H, m); 6.01 (1H, d); 6.3-6.6 (2H, m); 6.9-7.7 (10H,m).

Anal. Calculated for C 66.77 H 6.18 N 8.06 S 6.15 C₂₉H₃₂FN₃O₃S Found C67.13 H 6.57 N 8.22 S 6.53

MS ESI) m/z: 522 (MH⁺).

EXAMPLE 8 n-Butyl(2S)-2-{4-[(E-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acidand the appropriate amine using a similar method to that of Example 2.Yield: 42%

¹H NMR (CDCl₃, 400 MHz) δ: 0.93 (3H, t); 1.30-1.41 (2H, m); 1.54-1.64(2H, m); 1.75-1.87 (1H, m); 1.92-2.02 (1H, m); 2.03 (3H, s); 2.19 (2H,m); 4.02-4.15 (2H, m); 4.63-4.70 (1H, m); 4.75 (2H, d); 6.01 (1H, d);6.34-6.44 (1H, m); 6.52 (1H, d); 6.97 (1H, 7.07-7.16 (3H, m); 7.30 (1H,s); 7.35-7.44 (3H, m); 7.55 (1H, s); 7.64 (1H, d).

Anal. Calculated for C 65.99 H 6.33 N 8.24 S 6.29 C₂₈H₃₂FN₃O₃S Found C65.59 H 6.43 N 8.25 S 6.64

MS (ESI) m/z: 510 (MH⁺).

EXAMPLE 9 Prop-2-yl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acidand the appropriate amine using a similar method to that of Example 2.Yield: 52%

¹H NMR (CDCl₃, 400 MHz) δ: 1.24 (6H, m); 1.76-2.06 (2H, m); 2.05 (3H,s); 2.16-2.25 (2H, m); 4.59-4.66 (1H, m); 4.77 (2H, d); 4.99 (1H, m);6.05 (1H, d);6.36-6.46 (1H, m); 6.53 (1H, d); 6.99 (1H, s); 7.09-7.66(9H, m).

Anal. Calculated for C 65.13 H 6.13 N 8.44 S 6.44 C₂₇H₃₀FN₃O₃S, 0.16 H₂OFound C 65.28 H 6.26 N 8.50 S 6.05

MS (ESI) m/z: 496 (MH⁺).

EXAMPLE 10(2S)-2-{5-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 11 using a similar methodto that described in Example 1. Yield:35%.

¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.91-2.15 (2H, m); 2.04 (3H, s);2.5-2.66 (2H, m); 2.71-2.89 (2H, m); 2.89-3.11 (2H, m); 4.47-4.59 (1H,m); 5.03 (2H, d); 645-6.56 (1H, m); 6.75 (1H, d); 7.0-7.52 (7H, m); 6.74(1H, s); 7.80 (1H, s); 9.20 (1H, s).

Anal. Calculated for C 64.85 H 5.86 N 8.73 S 6.66 C₂₆H₂₈FN₃O₃S, 2.4 H₂OFound C 59.50 H 6.30 N 8.01 S 6.11

MS (ESI) m/z: 482 (MH⁺).

EXAMPLE 11 tert-Butyl(2S)-2-{5-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-4-methylsulfanylbutyrate

A solution of pentafluorophenyl5-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate(0.36 g, 0.7 mmol), L-methionine-tert-butyl ester(0.173 g, 0.84 mmol)and 1-hydroxy-7-azabenzotriazole (0.1 g, 0.73 mmol) in DMF (2 ml) wasstirred at ambient temperature overnight. After evaporation of thesolvent, the residue was taken up in ethyl acetate, washed with 5%sodium hydrogen carbonate solution and saturated brine and evaporated todryness. The residue was then purified by flash chromatography elutingwith dichloromethane/ethanol (97/3) to give the title compound. Yield:50%

¹H NMR (CDCl₃, 400 MHz) δ: 1.49 (9H, s); 1.9-2.3 (2H, m); 2.09 (3H, s);2.5-2.7 (2H, m); 2.8-3.2 (4H, m); 4.75 (3H, m); 6.2-6.6 (2H, m); 6.9-7.6(10H, m). MS (ESI) m/z: 538 (MH⁺).

The starting material was prepared as follows.

Methyl 5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoatewas prepared in a similar way to that described for methyl4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate inExample 2 but using 4-(4-fluorophenethyl)-3-methoxycarbonylbenzyltriphenylphosphonium bromide instead of3-(4-fluorophenyl)4-methoxycarbonylbenzyl triphenylphosphonium bromide.Yield: 70%

¹H NMR (CDCl₃, 400 MHz) δ: 2.8-2.95 (2H, m); 3.15-3.30 (2H, m); 3.89 and3.91 (3H, s); 4.7-4.85 (2H, m); 5.8-6.8 (2H, m); 6.9-7.85 (10H, m).

Sodium hydroxide (0.8 g, 20 mmol) in distilled water (3 ml) was added toa solution of methyl5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate (E andZ isomers) (2.4 g;.6.6 mmol) in methanol (30 ml). The mixture wasrefluxed for 6 hours. After evaporation and acidification with 12N HClto pH 6, the residue was extracted with dichloromethane and evaporatedto dryness to give5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoic acid(mixture of E and Z isomers).

¹H NMR (DMSOd₆+CF₃COOD) 400 MHz) δ: 2.75-2.90 (2H, m); 3.1-3.3 (2H, m);4.95-5.30 (2H, m); 5.90 and 6.5-6.85 (2H, m); 7-7.95 (10H, m); 9.2 (1H,m).

Pentafluorophenyl trifluoroacetate (1.47 ml; 8.6 mmol) was added to asolution of5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoic acid(2.5 g, 7.14 mmol) and pyridine (0.7 ml; 8.6 mmol) in DMF (7 ml). Afterstirring at ambient temperature overnight, the mixture was evaporated todryness and the residue extracted with ethyl acetate, washed withsaturated sodium hydrogen carbonate solution and saturated brine. Afterevaporation the reaction mixture was purified by flash chromatography,eluting with dichloromethane/ethanol (99/1) to give E isomerpentafluorophenyl5-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoateand Z isomer pentafluorophenyl5-[(Z)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate.Yield: 68%

E isomer: ¹H NMR (CDCl₃, 400 MHz) δ: 2.88 (2H, m); 3.26 (2H, m); 4.76(2H, m); 6.3-6.6 (2H, m); 6.9-7.8 (9H, m); 8.17 (1H, d).

Z isomer: ¹H NMR (CDCl₃, 400 MHz) δ: 2.90 (2H, m); 3.27 (2H, m); 4.82(2H, m); 5.89 (1H, m); 6.78 (1H, m); 6.9-7.6 (9H, m); 8.07 (1H, s).

EXAMPLE 12(2S)-2-{5-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-4-methylsulfonylbutyricAcid

The title compound was prepared from Example 13 using a similar methodto that described in Example 1. Yield: 60%.

¹H NMR (DMSO+CF₃COOD, 400 MHz) δ: 2.1-2.35 (2H, m); 2.7-3.1 (4H, m); 3.0(3H, s); 3.15-3.4 (2H, m); 4.55 (1H, m); 5.04 (2H, m); 6.4-6.8 (2H, m);7-7.5 (7H, m); 7.7-7.85 (2H, m); 8.8 (1H, m); 9.20 (1H, s).

Anal. Calculated for C 57.01 H 5.85 N 7.67 S 5.85 C₂₆H₂₈FN₃O₅S, 1.9 H₂OFound C 56.88 H 5.80 N 7.79 S 6.04

MS (ESI) m/z: 514 (MH⁺).

EXAMPLE 13 tert-Butyl(2S)-2-{5-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-4-methylsulfonylbutyrate

The title compound was prepared from pentafluorophenyl5-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoateusing a similar method to that described in Example 11. Yield: 44%

¹H NMR (CDCl₃, 400MHz) δ 1.47 (9H, s); 2.2-2.6 (2H, m); 2.8-3.3 (6H, m);2.92 (3H, s); 4.73 (3H, m); 6.2-6.6 (2H, m); 6.85-7.6 (10H, m).

Anal. Calculated for C 61.88 H 6.47 N 7.22 S 5.51 C₃₀H₃₆FN₃O₅S, 0.70 H₂OFound C 61.66 H 6.42 N 7.22 S 6.18

MS (ESI) m/z: 570 (MH⁺).

EXAMPLE 14(2S)-2-{5-[(Z)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 15 using a similar methodto that described in Example 1. Yield: 50%

¹HNMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.88-2.16 (2H, m); 2.04 (3H, s);2.50-2.71 (2H, m); 2.72-3.11 (4H, m); 4.47-4.62 (1H, m); 2H, m); 5.21(2H, d); 5.83-5.96 (6.80 (1H, d); 7.00-7.39 (7H, m); 7.32 (1H, s); 7.78(1H, s); 9.19 (1H, s).

Anal. Calculated for C 59.30 H 6.32 N 7.98 S 6.00 C₂₆H₂₈FN₃O₃S, 2.5 H₂OFound C 59.28 H 5.85 N 7.82 S 5.87

MS (ESI) m/z: 482 (MH⁺).

EXAMPLE 15 tert-Butyl(2S)-2-{5-[(Z)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from pentafluorophenyl5-[(Z)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoateand the appropriate amine using a similar method to that described inExample 11. Yield: 67%

¹H NMR (CDCl₃, 400 MHz) δ: 1.5 (9H, s); 2-2.4 (2H, m); 2.08 (3H, s);2.4-2.7 (2H, m); 2.8-3.2 (4H, m); 4.75 (3H, m); 5.85 (1H, m); 6.48 (1H,m); 6.6-7.6 (10H, m). MS (ESI) m/z: 538 (MH⁺).

EXAMPLE 16(2S)-2-{5-[(Z)-3-Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-4-methylsulfonylbutyricAcid

The title compound was prepared from Example 17 using a similar methodto that described in Example 1.

¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 2.1-2.4 (2H, m); 2.7-3.45 (6H, m);3.0 (3H, s); 4.55 (1H, m); 5.22 (2H, m); 5.92 (1H, m); 6.80 (1H, m);7-7.5 (7H, m); 7.75 (2H, d); 8.8 (1H, d); 9.18 (1H, s).

Anal. Calculated for C 58.74 H 5.69 N 7.90 S 6.03 C₂₆H₂₈FN₃O₅S, H₂OFound C 58.74 H 5.65 N 8.03 S 6.08

MS (ESI) m/z: 514 (MH⁺).

EXAMPLE 17 tert-Butyl(2S)-2-{5-[(Z)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-4-methylsulfonylbutyrate

The title compound was prepared from pentafluorophenyl5-[(Z)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoateand the appropriate amine using a similar method to that described inExample 11. Yield: 65%

¹H NMR (CDCl₃, 400 MHz) δ: 1.52 (9H, s); 2.2-2.6 (2H, m); 2.8-3.30 (6H,m); 3.05 (3H, s); 4.7-4.9 (3H, m); 5.85 (1H, m); 6.6-7.35 (11H, m); 7.49(1H, s).

Anal. Calculated for C 62.85 H 6.40 N 7.33 S 5.60 C₃₀H₃₆FN₃O₅S, 0.2 H₂OFound C 62.87 H 6.58 N 7.33 S 6.06

MS (ESI) m/z: 570 (MH⁺).

EXAMPLE 18(2S)-2-{4-[(E)-3-(1-Methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 19 using a similar methodto that described in Example 1.

¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.74-2.0 (2H, m); 2.01 (3H, s);2.16-2.37 (2H, m); 3.83 (3H, s); 3.98 (2H, d); 4.32 (1H, dd); 6.48-6.60(1H, m); 6.69 (1H, d); 7.13-7.26 (2H, m); 7.40 -7.57 (5H, m); 7.63 (1H,d); 7.67 (1H, d).

Anal. Calculated for C 61.50 H 5.84 N 8.61 S 6.57 C₂₅H₂₆FN₃O₃S, 1.15 H₂OFound C 61.53 H 6.08 N 8.54 S 6.57

MS (ESI) m/z: 468 (MH⁺).

EXAMPLE 19 tert-Butyl(2S)-2-{4-[(E)-3-(1-Methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[3-(1-methylimidazol-2-yl)prop-1-en-1-yl]-2-fluorophenyl)benzoic acidusing a similar method to that described in Example 2. Yield: 30%

¹H NMR (CDCl₃+CF₃COOD, 400 MHz) δ: 1.46 (9H, s); 1.75-1.99 (2H, m); 2.05(3H, s); 2.07-2.33 (2H, m); 3.86 (3H, s); 3.97 (2H, d); 4.59 (1H, dd);6.24-6.33 (1H, m); 6.63 (1H, d); 7.09-7.17 (3H, m); 7.29-7.44 (5H, m).

Anal. Calculated for C 64.95 H 6.65 N 7.84 S 5.98 C₂₉H₃₄FN₃O₃S, 0.3 H₂OFound C 64.85 H 6.52 N 7.81 S 5.94

MS (ESI) m/z: 524 (MH⁺).

The starting material was prepared as follows:

A mixture of 4-(4-fluorophenethyl)-3-methoxycarbonylbenzyltriphenylphosphonium bromide (27 g, 46 mmol), glycolaldehyde (7.2 g; 92mmol), potassium carbonate (13 g; 92 mmol) and 18-crown-6 (0.2 g) indichloromethane (300 ml) was stirred for 2 days at ambient temperatureunder argon atmosphere. After addition of distilled water andextraction, the solution was evaporated to dryness to give methyl2-(4-fluorophenyl)-4-(3-hydroxyprop-1-en-1-yl)benzoate which was used inthe next step without further purification.

A solution of methyl2-(4-fluorophenyl)-4-(3-hydroxyprop-1-en-1-yl)benzoate (17 g),triphenylphosphine (22.8 g; 87 mmol) and tetrabromomethane (28.8 g; 87mmol) in dichloromethane (200 ml) was stirred at 0° C. for 1 hour. Afterfiltration of the insoluble material and evaporation to dryness, theresidue was purified by flash chromatography eluting withdichloromethanelpetroleum ether (30/70) to give methyl2-(4-fluorophenyl)-4-(3-bromoprop-1-en-1-yl)benzoate as a mixture of Eand Z isomers.

¹H NMR (CDCl₃, 400 MHz) δ: 3.65 (3H, m); 4.15 (2H, m); 6.1-6.2 and6.4-6.7 (2H, m); 7-7.95 (7H, m). n-Butyl lithium (1.6 M solution inether, 30 ml) was added at −78° C. and under argon atmosphere to asolution of N-methylimidazole (3.2 ml; 40 mmol). After stirring at −78°C. for 45 minutes, zinc iodide (14 g; 44 mmol) in solution in THF (100ml) was added. The mixture was allowed to warm to ambient temperaturefor 1 hour, cooled down to −78° C., and a solution of copper (I) cyanide(0.72 g; 8 mmol) and lithium chloride (0.68 g; 1.6 mmol) in THF (10 ml)was then added at −78° C. followed by a solution of methyl2-(4-fluorophenyl)-4-(3-bromoprop-1-en-1-yl)benzoate (7 g; 20 mmol) inTHF (50 ml). The mixture was stirred at −78° C., for 30 minutes and for1 hour 30 minutes at room temperature. After evaporation of the solvent,the residue was treated with EDTA (17 g; 44 mmol) in distilled water (50ml) and extracted with dichloromethane. The organic layer was evaporatedand purified by flash chromatography eluting withdichloromethane/ethanol (98/2) to give methyl4-[3-(1-methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoateas a mixture of E and Z isomers. Yield: 71%

¹H NMR (CDCl₃, 400 MHz) δ: 3.5-3.8 (8H, m); 6.05 and 6.7 (1H, m);6.8-7.9 (9H, m).

Methyl4-[3-(1-methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate(5 g; 14.3 mmol) in solution in methanol (100 ml) was treated at refluxfor 4 hours with sodium hydroxide (1.2 g; 30 mmol) in solution indistilled water (10 ml). After evaporation to dryness, the residue wasacidified at pH 6 with 6 N HCl to give a solid which was triturated inwater and subsequently in ether to give4-[3-(1-methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoicacid as a solid (mixture of E and Z isomers).

¹H NMR (DMSOd₃+CF₃COOD, 400 MHz) δ: 3.82 and 3.84 (3H, s); 4.0 (2H, m);6.5-7.9 (11H, m). MS (ESI) m/z: 336 (MH⁺).

EXAMPLE 20(2S)-2-{4-[(E)-3-(Imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 21 using a similar methodto that described in Example 1. Yield: 34%

¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.73-2.08 (2H, m); 2.0 (3H, s);2.14-2.37 (2H, m); 3.93 (2H, d); 4.31 (1H, dd); 6.52-6.63 (1H, m); 6.71(1H, d); 7.14-7.24 (2H, m); 7.40-7.55 (5H, m); 7.63 (2H, s).

Anal. Calculated for C 59.99 H 5.66 N 8.74 S 6.67 C₂₄H₂₄FN₃O₃S, 1.2 H₂OFound C 59.99 H 5.65 N 8.62 S 6.42

MS (ESI) m/z: 454 (MH⁺).

EXAMPLE 21 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-2-yl)prop-1-en-1-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acidand the appropriate amine using a similar method to that described inExample 2. Yield: 75%

¹H NMR (CDCl₃, 400 MHz) δ: 1.42 (9H, s); 1.76-2.03 (2H, m); 2.05 (3H,s); 2.17-2.26 (2H, m); 3.70 (2H, d); 4.50-4.59 (1H, m); 6.04 (1H, d);6.39-6.49 (1H, m); 6.53 (1H, d); 7.0 (2H, s); 7.04-7.43 (6H, m); 7.59(1H, d).

Anal. Calculated for C 65.99 H 6.33 N 8.24 S 6.29 C₂₈H₃₂FN₃O₃S Found C65.64 H 6.50 N 8.16 S 5.33

MS (ESI) m/z: 510 (MH⁺).

The starting material was prepared as follows:

Methyl4-[(E)-3-(1-tritylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoatewas prepared from methyl2-(4-fluorophenyl)-4-(3-bromoprop-1-en-1-yl)benzoate using a similarmethod to that described for methyl4-[3-(1-methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoatein Example 21, but using N-tritylimidazole in replacement ofN-methylimidazole.

¹H NMR (CDCl₃+CF₃COOD, 400 MHz) δ: 3.66 (2H, m); 3.68 (3H, s); 6.14 (1H,d); 7-7.9 (25H, m). MS (ESI) m/z: 579 (MH⁺).

A solution of methyl4-[(E)-3-(1-tritylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate(5.78 g; 6.5 mmol), acetic acid (5 ml) and 12N HCl (5 ml) in methanol(100 ml) was refluxed for 1 hour 30 minutes. After evaporation todryness, the residue was neutralised with aqueous NH₄ OH, extracted withdichloromethane, evaporated and purified by flash chromatography,eluting with dichloromethane/ethanol (98/2) to give methyl4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate.Yield: 63%

¹H NMR (CDCl₃, 400 MHz) δ: 3.72 (3H, s); 3.91 (2H, m); 6.28 (1H, m);6.67 (1H, d); 7-7.45 (8H, m); 7.75 (1H, d).

A solution of methyl4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (1.37g; 4 mmol) in methanol (20 ml) was treated at reflux for 4 hours with asolution of sodium hydroxide (0.32 g; 8 mmol) in water (24 ml). Afterevaporation to dryness the residue was acidified at pH 6 with 12N HCl.The resulting solid was triturated with water and subsequently withether to give4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid.Yield: 46%

¹H NMR (DMSOd₃+CF₃COOD, 400 MHz) δ: 3.94 (2H, m); 6.4-6.8 (1H, m); 7-7.9(10H, m).

EXAMPLE 22(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-difluorolphenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 23 using a similar methodto that described in Example 1. Yield: 64%.

¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.73-2.03 (2H, m); 2.02 (3H, s);2.23-2.43 (2H, m); 4.32 (1H, dd); 5.06 (2H, d); 6.62-6.73 (1H, m); 6.78(1H, d); 7.03-7.14 (1H, m); 7.16-7.28 (1H, m); 7.35-7.44 (1H, m); 7.49(1H, s); 7.55-7.65 (2H, m); 7.74 (1H, s); 7.81 (1H, s); 9.21 (1H, s).

Anal. Calculated for C 59.99 H 5.03 N 8.74 S 6.67 C₂₄H₂₃F₂N₃O₃S, 0.5 H₂OFound C 60.19 H 5.11 N 8.65 S 6.28

MS (ESI) m/z: 472 (MH⁺).

EXAMPLE 23 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-difluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-difluorophenyl)benzoicacid and the appropriate amine using a similar method to that describedin Example 2. Yield: 74%

¹H NMR (CDCl₃, 400 MHz) δ: 1.44 (9H, s); 1.79-2.12 (2H, m); 2.07 (3H,s); 2.25-2.42 (2H, m); 4.53-4.62 (1H, m); 4.75 (2H, d); 6.27 (1H, d);6.33-6.44 (1H, m); 6.51 (1H, d); 6.82-7.04 (3H, m); 7.11 (1H, s);7.27-7.38 (2H, m); 7.40 -7.48 (11H, dd); 7.55 (1H, s); 7.67 (1H, d).

Anal. Calculated for C 63.74 H 5.92 N 7.96 S 6.08 C₂₈H₃₁F₂N₃O₃S Found C63.38 H 5.90 N 7.85 S 5.72

MS (ESI) m/z: 528 (MH⁺).

The starting material was prepared as follows:

A mixture of 2-(imidazol-1-yl)acetaldehyde (2.32 g; 76 mmol),4-methoxycarbonyl-3-(4-trifluoromethylsulphonyloxy)benzyltriphenylphosphonium bromide (5.27 g; 37 mmol), potassium tert-butoxide(1.2 g; 10 mmol) in dichloromethane (30 ml) was stirred under argonatmosphere at ambient temperature for 7 hours. After filtration of theinsoluble, and evaporation, the residue was purified by flashchromatography eluting with isopropanol/dichloromethane (4/96) to givemethyl4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(trifluoromethylsulphonyloxy)benzoateas a mixture of E and Z isomers.

¹H NMR (CDCl₃, 400 MHz) δ: 3.98 (3H, s); 4.80 (2H, m); 6-8.2 (8H, m).

A mixture of methyl4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(trifluoromethylsulphonyloxy)benzoate(1.17 g; 3 mmol), 2,4-difluorophenylboronic acid (0.52 g; 3.3 mmol),tetrakis(triphenylphosphine) palladium (0.14 g; 0.12 mmol), 2M aqueoussodium carbonate solution (4.5 ml), lithium chloride (0.25 g; 6 mmol)and ethanol (13 ml) in toluene (120 ml) was refluxed, under an argonatmosphere, for 8 hours. The mixture was extracted with ethyl acetateand purified by flash chromatography eluting withisopropanol/dichloromethane (3/97) to give methyl4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-difluorophenyl)benzoateas a mixture of E and Z isomers.

¹HNMR (CDCl₃, 400 MHz) δ: 3.71 (3H, s); 4.7-4.9 (2H, M); 5.9-6 (1H, m);6.48.1 (10H, m).

A solution of methyl4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-difluorophenyl)benzoate(0.9 g; 2.54 mmol) and 2N sodium hydroxide solution (3.8 ml) in methanolwas heated at reflux for 7 hours. After evaporation of the solvent andneutralisation to pH 6.5 with 6N HCl, the residue was purified onreverse phase silica eluting with methanol/ammonium carbonate buffer (2g/l, pH 7) (50/50) to give4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-difluorophenyl)benzoicacid after freeze-drying. Yield: 49%.

¹H NMR (DMSO+CF₃COOD, 400 MHz) δ: 5.06 (2H, m); 6.75 (2H, m); 7-8 (8H,m); 9.20 (1H, s).

Example Ar R R1 22 2,4-difluorophenyl H SCH₃ 23 2,4-difluorophenyl t-BuSCH₃ 24 2-thienyl t-Bu SCH₃ 25 4-chlorophenyl H SCH₃ 26 4-chlorophenylt-Bu SCH₃ 27 3-chloro-4-fluorophenyl H SCH₃ 28 3-chloro-4-fluorophenylt-Bu SCH₃ 29 2,4-dichlorophenyl H SCH₃ 30 2,4-dichlorophenyl t-Bu SCH₃31 2,4-dichlorophenyl t-Bu SO₂CH₃ 32 3-thienyl H SCH₃ 33 3-thienyl t-BuSCH₃ 34 3-chlorophenyl H SCH₃ 35 3-chlorophenyl t-Bu SCH₃

EXAMPLE 24 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(thien-2-yl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared using a similar method to that describedin Example 23, except using the appropriate boronic acid in place of2,4-difluorophenylboronic acid.

Yield: 53%; ¹H NMR (CDCl₃, 400 MHz) δ: 1.43 (9H, s); 1.78-2.08 (2H, m);2.05 (3H, s); 2.19-2.32 (2H, m); 4.58-4.66 (1H, m); 4.75 (2H, d); 6.18(1H, d); 6.33-6.44 (1H, m); 6.51 (1H, d); 6.97 (1H, s); 6.04-6.18 (3H,m); 6.35-6.45 (3H, m); 7.55 (1H, s); 7.61 (1H, d).

Anal. Calculated for C 62.75 H 6.28 N 8.44 S 12.89 C₂₆H₃₁N₃O₃S₂ Found C62.01 H 6.91 N 8.62 S 12.65

MS (ESI) m/z: 498 (MH⁺).

EXAMPLE 25(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-chlorophenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 26 as described for Example1.

Yield: 54%; ¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.75-2.05 (2H, m); 2.02(3H, s); 2.15-2.40 (2H, s); 4.26-4.37 (1H, s); 5.06 (2H, s); 6.62-6.74(1H, m); 6.79 (1H, d); 7.38-7.62 (7H, m); 7.75 (1H, s); 7.81 (1H, s);9.22 (1H, s).

Anal. Calculated for C 59.51 H 5.15 N 8.67 S 6.62 C₂₄H₂₄ClN₃O₃S, 0.8 H₂OFound C 59.14 H 5.17 N 9.41 S 5.96

MS (ESI) m/z: 469 (MH⁺).

EXAMPLE 26 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-chlorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared using a similar method to that describedin Example 23, except using the appropriate boronic acid in place of2,4-difluorophenylboronic acid.

Yield: 78%; ¹H N (CDCl₃, 400 MHz) δ: 1.43 (9H, s); 1.76 (2H, m); 2.06(3H, s); 2.22 (2H, m); 4.52-4.59 (1H, m); 4.76 (2H, d); 6.03 (1H, d);6.34-6.45 (1H, m); 6.97 (1H, s); 7.12 (1H, s); 7.25-7.46 (6H, m); 7.55(1H, s); 7.64 (1H, d).

Anal. Calculated for C 63.93 H 6.13 N 7.99 S 6.09 C₂₈H₃₂ClN₃O₃S Found C63.93 H 6.27 N 8.16 S 5.89

MS (ESI) m/z: 527 (MH⁺).

EXAMPLE 27(2S)-2-{4-[(E)-3-Imidazol-1-yl)prop-1-en-1-yl]-2-(3-chloro-4-fluorophenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 28 as described for Example1.

Yield: 71%; ¹H NMR (DMSOd₃+CF₃COOD, 400 MHz) δ: 1.74-2.05 (2H, m); 2.00(3H, s); 2.15-2.37 (2H, m);4.28-4.37 (1H, m); 5.06 (2H, d); 6.64-6.74(1H, m); 6.78 (1H, d); 7.35-7.63 (6H, m); 7.75 (1H, s); 7.81 (1H, s);9.21 (1H, s).

Anal. Calculated for C 55.01 H 5.19 N 8.02 S 6.12 C₂₄H₂₃ClFN₃O₃S, 2 H₂OFound C 52.64 H 4.46 N 7.80 S 5.76

MS (ESI) m/z: 480 (MH⁺).

EXAMPLE 28 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(3-chloro-4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared using a similar method to that describedin Example 23, except using the appropriate boronic acid in place of2,4-difluorophenylboronic acid.

Yield: 83%; ¹H NMR (CDCl₃, 400 MHz) δ: 1.43 (9H, s); 1.77-2.15 (4H, m);2.06 (3H, s); 2.21-2.37 (2H, m); 4.51-4.63 (1H, m); 4.75 (2H, d); 6.13(1H, d); 6.34-6.44 (1H, m); 6.50 (1H, d); 6.97 (1H, s); 7.12 (1H, s);7.14-7.33 (3H, m); 7.38-7.49 (2H, m); 7.55 (1H, s); 7.61 (1H, d).

Anal. Calculated for C 61.81 H 5.74 N 7.72 S 5.89 C₂₈H₃₁ClFN₃O₃S Found C61.45 H 5.91 N 7.67 S 5.81

MS (ESI) m/z: 544 (MH⁺).

EXAMPLE 29(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-dichlorophenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 30 as described for Example1.

Yield: 63%; ¹H NMR (DMSOd₃+CF₃COOD, 400 MHz) δ: 1.77-2.08 (2H, m); 2.02(3H, s); 2.27-2.55 (2H, m); 4.27-4.36 (1H, m); 5.05 (2H, d); 6.59-6.69(1H, m); 6.78 (1H, d); 7.29-7.82 (8H, m);9.17(1H, s).

Anal. Calculated for C 57.15 H 4.60 N 8.33 S 6.33 C₂₄H₂₃Cl₂N₃O₃S 0.7 H₂OFound C 55.42 H 4.78 N 8.40 S 6.20

MS (ESI) m/z: 505 (MH⁺).

EXAMPLE 30 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-dichlorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared using a similar method to that describedin Example 23, except using the appropriate boronic acid in place of2,4-difluorophenylboronic acid.

Yield: 85%; ¹H N (CDCl₃, 400 MHz) δ: 1.43 (9H, s); 1.70-2.43 (4H, m);2.44 (3H, s); 4.45-4.59 (1H, s); 4.73 (2H, d); 6.08-6.28 (1H, m);6.31-6.42 (1H, m); 6.51 (1H, d); 6.95 (1H, s); 7.10 (1H, s); 7.19-7.50(3H, m); 7.41-7.50 (2H, m); 7.52 (1H, s); 7.62-7.77 (1H, m).

Anal. Calculated for C 60.00 H 5.57 N 7.50 S 5.72 C₂₈H₃₁Cl₂N₃O₃S Found C59.97 H 5.74 N 7.58 S 5.64

MS (ESI) m/z: 560 (MH⁺).

EXAMPLE 31 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-1-yl]-2-(2,4-dichlorophenyl)benzamido}-4-methylsulfonylbutyrate

The title compound was prepared from Example 30 as described for Example4.

Yield: 71%; ¹H NMR (CDCl₃, 400 MHz) δ: 1.45 (9H, s); 1.90-2.10 (1H, m);2.24-2.45 (1H, m); 2.65-3.12 (7H, m); 4.41-4.59 (1H, m); 4.73 (2H, d);6.18-6.54 (3H, m); 6.95 (1H, s); 7.10 (1H, s); 7.15-7.80 (7H, m).

Anal. Calculated for C 56.76 H 5.27 N 7.09 S 5.41 C₂₈H₃₁Cl₂N₃O₃S Found C56.83 H 5.52 N 7.00 S 5.79

MS (ESI) m/z: 592 (MH⁺).

EXAMPLE 32(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(thien-3-yl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 33 as described for Example1.

Yield: 53%; ¹H NMR (CDCl₃, 400 MHz) δ: 1.43 (9H, s); 1.75-2.04 (2H, m);2.06 (3H, s); 2.18-2.28 (2H, m); 4.55-4.62 (1H, m); 4.75 (2H, d); 6.08(1H, d); 6.33-6.43 (1H, m); 6.51 (1H, d); 6.97 (1H, s); 7.11 (1H, s);7.14-7.19 (1H, m); 7.33-7.41 (4H, m); 7.55 (1H, s); 7.63 (1H, d).

Anal. Calculated for C 59.84 H 5.25 N 9.52 S 14.52 C₂₂H₂₃N₃O₃S₂ Found C57.81 H 5.49 N 9.15 S 14.06

MS (ESI) m/z: 442 (MH⁺).

EXAMPLE 33 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(thien-3-yl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared using a similar method to that describedin Example 23, except using the appropriate boronic acid in place of2,4-difluorophenylboronic acid.

Yield: 72%; ¹H NMR (DMSOd₃+CF₃COOD, 400 MHz) δ: 1.80-2.10 (2H, m); 2.03(3H, s); 2.28-2.51 (2H, m); 4.33-4.45 (1H, m); 5.06 (2H, d); 6.62-6.72(1H, m); 6.78 (1H, d); 7.30 (1H, d); 7.99 (1H, d); 7.46-7.57 (2H, m);7.60-7.66 (2H, m); 7.75 (1H, s); 7.28 (1H, s); 8.65 (1H, d); 9.22 (1H,s).

Anal. Calculated for C 62.75 H 6.28 N 8.44 S 12.89 C₂₆H₃₁N₃O₃S₂ Found C62.31 H 6.45 N 8.38 S 12.72

MS (ESI) m/z: 498 (MH⁺).

EXAMPLE 34(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(3-chlorophenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 35 as described for Example1.

Yield: 56%; ¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.75-2.04 (2H, m); 2.10(3H, s); 2.15-2.40 (2H, m); 4.25-4.40 (1H, dd); 5.06 (2H, d); 6.6-6.9(2H, m); 7.28-7.70 (7H, m); 7.75 (1H, s); 7.81 (1H, s); 9.22 (1H, s). MS(ESI) m/z: 470 (MH⁺).

EXAMPLE 35 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl-2-(3-chlorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared using a similar method to that describedin Example 23, except using the appropriate boronic acid in place of2,4-difluorophenylboronic acid.

Yield: 74%; ¹H NMR (CDCl₃, 400 MHz) δ: 1.4 (9H, s); 1.74-1.88 (1H, m);1.89-2.05 (1H, m); 2.04 (3H, s); 2.13-2.28 (2H, m); 4.5-4.6 (1H, m);4.78 (2H, d); 6.04 (1H, d); 6.3-6.6 (2H, m); 6.90 (1H, s); 7.12 (1H, s);7.2-7.5 (6H, m); 7.55 (1H, s); 7.64 (1H, d).

Anal. Calculated for C 63.93 H 6.13 N 7.99 C₂₈H₃₂ClN₃O₃S Found C 63.75 H6.16 N 8.08

MS (ESI) m/z: 526 (MH⁺).

EXAMPLE 36(2S)-2-{4-[(E)-3-(Imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 37 as described for Example1.

Yield:42%; ¹H NMR (DMSOd₃+CF₃COOD, 400 MHz) δ: 1.72-2.13 (2H, m); 2.01(3H, s); 2.1-2.4 (2H, m); 3.66 (2H, d); 4.23-4.44 (1H, m); 6.45-6.72(2H, m); 7.08-7.30 (2H, m); 7.31-7.69 (6H, m); 9.06 (1H, s).

Anal. Calculated for C 61.37 H 5.54 N 8.95 S 6.83 C₂₄H₂₄CN₃O₃S 0.9 H₂OFound C 61.07 H 5.17 N 8.87 S 6.62

MS (ESI) m/z: 454 (MH⁺).

EXAMPLE 37 tert-Butyl(2S)-2-{4-[(E)-3-(Imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acidand the appropriate amine as described for Example 2.

Yield: 46%; ¹H NMR (CDCl₃+CF₃COOD, 400 MHz) δ: 1.48 (9H, s); 1.7-2.0(2H, m); 2.06 (3H, s); 2.05-2.26 (2H, m); 3.62-3.81 (3H, m); 4.54-4.67(1H, m); 6.26-6.45 (1H, m); 7.03-7.66 (8H, m); 8.78 (1H, s). 6.65 (1H,d);

Anal. Calculated for C 65.99 H 6.33 N 8.24 S 6.29 C₂₈H₃₂FN₃O₃S Found C65.61 H 6.18 N 8.24 S 5.73

MS (ESI) m/z: 510 (MH⁺).

The starting material was prepared as follows:

Ethyl magnesium bromide (3M solution in ether; 5.7 ml; 17 mmol) wasadded dropwise at 0° C. under argon atmosphere to a solution of N-trityl5-iodoimidazole (6.1 g; 14 mmol). After stirring at 0° C. for 1 hour, asolution of copper (I) cyanide (0.27 g; 3 mmol) and lithium chloride(0.252 g; 6 mmol) in THF (5 ml) was added. The mixture was cooled downto −78° C. and a solution of methyl4-(3-bromoprop-1-en-1-yl)-2-(4-fluorophenyl)benzoate (3.5 g; 10 mmol) inTHF (10 ml) was added. After stirring at −78° C. for 15 minutes, thetemperature was allowed to raise to room temperature. The mixture wasstirred further overnight. After addition of aqueous ammonium chloridesolution and evaporation to dryness, the residue was extracted withdichloromethane/distilled water. The organic layer was evaporated togive methyl4-[(E)-3-(1-tritylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoatewhich was used in the next step without further purification.

¹H NMR (CDCl₃+CF₃COOD, 400 MHz) δ: 1.48 (9H, s); 3.60-3.82 (5H, m);7.00-7.85 (26H, m).

A solution of methyl4-[(E)-3-(1-tritylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate(7.8 g; 10 mmol), 12N HCl (7.5 ml) and acetic acid (7.5 ml) in methanol(150 ml) was refluxed for 1 hour 30 minutes. After evaporation todryness and neutralisation with an aqueous solution of ammoniumhydroxide, the residue was extracted with dichloromethane and purifiedby flash chromatography, eluting with a gradient 2-5%ethanol/dichloromethane to give methyl4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate.Yield: 20%.

¹H NMR (CDCl₃, 400 MHz) δ: 3.5-3.8 (5H, m); 6.58 (2H, m); 6.8-7.9 (9H,m).

A solution of methyl4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (0.6g; 1.8 mmol) in 1N HCl (15 ml) was refluxed for 20 hours. The mixturewas evaporated to dryness to give4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acidas the hydrochloride salt.

¹H NMR (DMSOd₃+CF₃COOD, 400 MHz) δ: 3.6-3.7 (2H, m); 6.62 (2H, s);7.1-7.9 (8H, m); 9.06 (1H, s).

EXAMPLE 38(2S)-2-{4-[(E)-3-(1-Methylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 39 as described for Example1.

¹H NMR (DMSO+CF₃COOD, 400 MHz) δ: 1.74-2.03 (2H, m); 2.01 (3H, s); 3.69(2H, d); 3.81 (3H, s); 4.28-4.35 (1H, dd); 6.50-6.66 (2H, m); 7.13-7.24(2H, m); 7.37-7.60 (6H, m); 9.06 (1H, s).

Anal. Calculated for C 61.38 H 5.85 N 8.59 S 6.55 C₂₅H₂₆FN₃O₃S, 1.2 H₂OFound C 61.00 H 5.94 N 8.57 S 6.53

MS (ESI) m/z: 468 (MH⁺).

EXAMPLE 39 tert-Butyl(2S)-2-{4-[(E)-3-(1-methylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[3-(1-methylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoicacid and the appropriate amine as described for Example 2.

¹H NMR (CDCl₃, 400 MHz) δ: 1.42 (9H, s); 1.72-1.88 (1H, m); 1.89-2.02(1H, m); 2.04 (3H, s); 2.14-2.26 (2H, m); 3.52 (2H, d); 3.57 (3H, s);4.50-4.57 (1H, m); 5.97 (1H, d); 6.35-6.43 (2H, m); 6.80-7.52 (8H, m);7.62 (1H, d).

Anal. Calculated for C 65.17 H 6.64 N 7.86 S 6.00 C₂₉H₃₄FN₃O₃S, 0.6 H₂OFound C 65.14 H 6.97 N 7.89 S 6.46

MS (ESI) m/z: 524 (MH⁺).

The starting material was prepared as follows:

Methyl4-[3-(1-methylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoatewas prepared from methyl4-(3-bromoprop-1-en-1-yl)-2-(4-fluorophenyl)benzoate and5-iodo-1-methyl-imidazole using a similar method to that described formethyl4-[(E)-3-(1-tritylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoatein Example 37.

Yield: 59%; MS (ESI) m/z: 351 (MH⁺).

4-[3-(1-Methylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoicacid was prepared from methyl4-[3-(1-methylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoateusing a similar method to that described for4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acidin Example 37.

MS (ESI) m/z: 337 (MH⁺).

EXAMPLE 40(2S)-2-{4-[(E)-3-(1-Benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyricAcid

The title compound was prepared from Example 41 as described for Example1.

¹H NMR (DMSO, 400 MHz) δ: 1.7-2.1 (2H, m); 2.01 (3H, s); 2.1-2.4 (2H,m); 4.02 (2H, d); 4.32 (1H, m); 5.49 (2H, s); 6.26-6.44 (1H, m); 6.60(1H, d); 7.13-7.61 (12H, m); 7.72 (1H, d); 7.77 (1H, d).

Anal. Calculated for C 65.24 H 5.83 N 7.36 C₃₁H₃₀FN₃O₃S 1.5 H₂O Found C65.04 H 5.42 N 7.21

MS (ESI) m/z: 544 (MH⁺).

EXAMPLE 41 tert-Butyl(2S)-2-{4-[(E)-3-(1-Benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate

The title compound was prepared from4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoicacid and the appropriate amine as described for Example 2.

Yield: 17%; ¹H NMR (CDCl₃, +CF₃COOD, 400 MHz) δ: 1.46 (9H, s); 1.7-2.3(4H, m); 2.05 (3H, s); 3.95 (2H, d); 4.56-4.64 (1H, m); 5.28 (2H, s);6.12-6.24 (1H, m); 6.55 (1H, d); 6.98-7.60 (14H, m).

Anal. Calculated for C 68.85 H 6.47 N 6.88 S 5.25 C₃₅H₃₈FN₃O₃S 0.6 H₂OFound C 68.83 H 6.68 N 7.18 S 5.50

MS (ESI) m/z: 601 (MH⁺).

The starting material was prepared as follows:

Methyl4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoatewas prepared from methyl4-(3-bromoprop-1-en-1-yl)-2-(4-fluorophenyl)benzoate as described formethyl4-[3-(1-methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoatein Example 19, but using N-benzylimidazole. Yield: 76%

¹H NMR (CDCl₃, +CF₃COOD, 400 MHz) δ: 3.69 (3H, s); 4.01 (2H, m); 5.28(2H, s); 6.14 (1H, m); 6.52 (1H, m); 7.0-7.9 (14H, m). MS (ESI) m/z: 427(MH⁺).

A solution of methyl4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate(3 g; 7 mmol), sodium hydroxide (0.8 g; 20 mmol) and distilled water (5ml) in methanol (50 ml) was refluxed for 4 hours. After evaporation todryness and acidification to pH 6 with 6N HCl, the resulting solid wastriturated with water and ether to give4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoicacid as a mixture of E and Z isomers.

¹H NMR (DMSO, 400 MHz) δ: 4.04 (2H, m); 5.50 (2H, s); 6.3-7.9 (16H, m).MS (ESI) m/z: 413 (MH⁺).

EXAMPLE 42(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyricAcid

A solution of tert-butyl(2S)-2-{4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate(0.2 g; 0.4 mmol) in dichloromethane (2 ml) was treated at 0° C. withTFA (2 ml). The mixture was allowed to warm to ambient temperature andstirred for 1 hour. After evaporation of the solvent, the residue wastaken up with distilled water (5 ml); the pH was adjusted to 6 withNH₄OH and the solution was purified on reverse phase silica eluting withmethanol/ammonium carbonate buffer (2 g/l; pH 7) (40/60) to give thetitle compound after freeze-drying. Yield: 40%

¹H NMR (DMSO+CF₃COOD, 400 MHz) δ: 1.8-2 (2H, m); 2 (3H, s); 2.15-2.4(2H, m); 4.32 (1H, m); 5.05 (2H, m); 6.6-6.85 (2H, m); 7.20 (2H, m);7.4-7.6 (5H, m); 7.7-7.85 (2H, m); 9.21 (1H,s).

Anal. Calculated for C 60.90 H 5.58 N 8.88 S 6.77 C₂₄H₂₄N₃O₃SF 1.11 H₂OFound C 60.80 H 5.32 N 8.83 S 6.37

MS (FSI) m/z: 454 (MH⁺).

EXAMPLE 43(2S)-2-{4-[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutan-1-ol

A solution of lithium borohydride (0,066 g; 3 mmol) in diethyl ether (15ml) was added at 0° C. to a solution of Example 2 (0,74 g, 1.6 mmol) inTHF (40 ml). After stirring at ambient temperature overnight the mixturewas acidified at pH 8 with 12N HCl and evaporated to dryness. Theresidue was taken up in dichloromethane/methanol (90/10). Afterevaporation of the solvent, the compound was purified on reverse phasesilica eluting with methanol/ammonium carbonate (2 g/l pH 7) buffer. Theappropriate fractions were concentrated under vacuum and extracted withdichloromethane and evaporated to give the title compound as a solid.Yield: 36%

¹H NMR (CDCl₃, 400 MHz) δ: 1.4-1.8 (2H, m); 2.04 (3H, s); 2.2-2.4 (2H,m); 3.48 (2H, m); 4.02 (1H, m); 4.74 (2H, m); 5.62 (1H, d); 6.3-6.6 (2H,m); 6.96 (1H, m); 7-7.77 (9H, m).

Anal. Calculated for C 64.52 H 6.07 N 9.41 S 7.18 C₂₄H₂₆FNSO₂S, 0.4 H₂OFound C 64.75 H 6.10 N 9.50 S 7.23

MS (ESI) m/z: 440 (MH⁺).

EXAMPLE 44(3S)-3-{4-[(E)-3-(Imidazol-1-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-5-methylsulfanyl-1-phenyl-2-pentanone

A mixture of4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid(0.65 g, 2 mmol), (2S)-3-amino-5-methylsulfanyl-1-phenyl-2-pentanone(0.62 g, 2.4 mmol), HOBT (0.3 g, 2.2 mmol), EDC (0.425 g, 2.2 mmol),DMAP (0.245 g, 2 mmol) in dichloromethane (20 ml) was stirred at roomtemperature overnight. The reaction mixture was extracted withdichloromethane, evaporated to dryness and purified by flashchromatography eluting with dichloromethane/ethanol (97/3) to give thetitle compound. Yield: 35%

¹H NMR (CDCl₃, 400 MHz) δ: 1.7-1.9 (2H, m); 2.05 (3H, s); 2-2.2 (2H, m);3.78 (2H, m); 4.7-4.9 (3H, m); 6.12 (1H, m); 6.30-6.6 (2H, m); 6.96 (1H,s); 7-7.7 (14H, m).

Anal. Calculated for C 69.61 H 5.80 N 7.86 S 5.99 C₃₁H₃₀FNO₃O₂S, 0.4distilled water Found C 69.79 H 5.80 N 8.00 S 6.37

MS (ESI) m/z: 528 (MH⁺).

The starting material was prepared as follows:

A solution of DEBAL in hexane (440 ml) was added dropwise at −70° C.under argon atmosphere to a suspension of ethyl 2-(imidazol-1-yl)acetate(27.13 g; 0. 176 mole) in ether (1.21). The mixture was stirred at −70°C. for 2 hours 30 minutes. Methanol (100 ml) and distilled water (8 ml)were then added at −70° C. and the mixture was allowed to warm toambient temperature and stirred for 2 hours. The resulting precipitatewas filtered, washed with dichloromethane/methanol (2×400 ml) and thefiltrate was evaporated and purified by flash chromatography elutingwith a gradient 10-25% methanol/dichloromethane to give2-(imidazol-1-yl)acetaldehyde which was isolated as the hemiacetal2-(imidazol-1-yl)-1-methoxyethanol. Yield: 68%

¹H NMR (CDCl₃, 400 Hz) δ: 3.48 (3H, s); 4.02 (2H, d); 6.9-7.5 (3H, m).

A solution of 2-(imidazol-1-yl)acetaldehyde (2.6 g; 0.0 18 mmol),3-(4-fluorophenyl)-4-methoxycarbonylbenzyl triphenylphosphonium bromide(5.4 g; 0.09 mmol), potassium carbonate (1.38 g; 0.01 mmol) and 18crown-6 (0.1 g; 0.37 mmol) in THF (150 ml) was stirred under argonatmosphere at ambient temperature overnight. After filtration of theinsoluble material and evaporation to dryness, the residue was purifiedby flash chromatography eluting with a mixture ofdichloromethane/ethanol (98/2) to give methyl4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate as amixture of E and Z isomers. Yield: 93%

A solution of methyl4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (E and Zisomers) (1.9 g; 5.6 mmol) and 2N aqueous sodium hydroxide solution (8.5ml; 17 mmol) in methanol (100 ml) was refluxed for 9 hours. Afterevaporation and acidification with 12N HCl (1.5 ml), the resulting solidwas washed with distilled water and ether, taken up indichloromethane/methanol (99/1) to give4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid(E isomer) after evaporation as a foam. Yield: 89%.

¹H NMR (DMSO+CF₃COOD, 400 MHz) δ: 5.06 (2H, d); 6.7-7.85 (2H, m);7.1-7.9 (9H, m); 9.22 (1H, s).

EXAMPLE 45(3S)-3-{5-[(Z)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-5-methylsulfanyl-1-phenyl-2-pentanone

A solution of pentafluorophenyl5-[(Z)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate(0.25 g, 0.5 mmol), (3S)-5-methylsulfanyl-2-oxo-1-phenylpentan-3amine(0.16 g, 0.6 mmol), 1-hydroxy-7-azabenzotriazole (0.075 g, 0.55 mmol) inDMF (2 ml) was stirred at ambient temperature overnight. Afterevaporation of the solvent, the residue was taken up in ethyl acetate,washed with 5% sodium hydrogen carbonate and saturated sodium chlorideand evaporated to dryness. The residue was then purified by flashchromatography eluting with dichloromethane/ethanol (97/3) to give thetitle compound which was isolated as the hydrochloride salt by treatmentwith HCl/ether. Yield: 70%

¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.83-2.20 (2H, m); 2.04 (3H, s);2.05-3.11 (6H, m); 3.99 (2H, s); 4.74 (1H, dd); 5.23 (2H, d); 5.85-5.96(1H, m); 6.99-7.10 (2H, m); 7.13-7.44 (10H, m); 7.73 (1H, s); 7.78 (1H,s); 9.21 (1H, s).

Anal. Calculated for C 65.92 H 5.91 N 6.99 S 5.33 Cl 7.37 C₃₃H₃₄FN₃O₂S1.25 HCl Found C 66.03 H 6.20 N 6.97 S 5.57 Cl 7.56

MS (ESI) m/z: 556 (MH⁺).

The starting material was prepared as follows:

A solution of 2-(imidazol-1-yl)acetaldehyde (2.8 g; 0.021 mmol),4-(4-fluorophenethyl)-3-methoxycarbonylbenzyl triphenylphosphoniumbromide (6.2 g; 0.01 mmol), potassium carbonate (2.8 g; 0.02 mmol) and18 crown-6 (0.1 g; 0.37 mmol) in dichloromethane (100 ml) was stirredunder argon atmosphere at ambient temperature overnight. Afterextraction and evaporation to dryness, the residue was purified by flashchromatography eluting with a mixture of dichloromethane/ethanol (98/2)to give methyl5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate as amixture of E and Z isomers.

Yield: 70%; ¹H NMR (CDCl₃, 400 MHz) δ: 2.8-2.95 (2H, m); 3.15-3.30 (2H,m); 3.89 and 3.91 (3H, s); 4.7-4.85 (2H, m); 5.8-6.8 (2H, m); 6.9-7.85(10H, m).

A solution of methyl5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate (E andZ isomers) (2.4 g; 6.6 mmol) in methanol (100 ml) was treated with asolution of sodium hydroxide (0.8 g; 20 mmol) in water (3 ml). Themixture was refluxed for 9 hours. After evaporation and acidificationwith 12N HCl (1.5 ml), the residue was extracted with dichloromethane togive after evaporation5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoic acid asa mixture of E and Z isomers.

¹H NMR (DMSOd₆+CF₃COOD) 400 MHz) δ: 2.75-2.90 (2H, m); 3.1-3.3 (2H, m);4.95-5.30 (2H, m); 5.90 and 6.5-6.85 (2H, m); 7-7.95 (10H, m); 9.2 (1H,m). MS (ESI) m/z: 351 (MH⁺).

Pentafluorophenyl trifluoroacetate (1.47 ml; 8.6 mmol) was added to asolution of5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoic acid(2.5 g, 7.14 mmol) and pyridine (0.7 ml; 8.6 mmol) in DMF (7 ml). Afterstirring at ambient temperature overnight, the mixture was evaporated todryness and the residue extracted with ethyl acetate, washed withsaturated sodium hydrogen carbonate and saturated sodium chloride. Afterevaporation the reaction mixture was purified by flash chromatographyeluting with dichloromethane/ethanol (99/1) to give E isomerpentafluorophenyl5-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoateand Z isomer pentafluorophenyl5-[(Z)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate.Yield: 68%

E isomer: ¹H NMR (CDCl₃, 400 MHz) δ: 2.88 (2H, m); 3.26 (2H, m); 4.76(2H, m); 6.3-6.6 (2H, m); 6.9-7.8 (9H, m); 8.17 (1H, d).

Z isomer: ¹H NMR (CDCl₃, 400 MHz) δ: 2.90 (2H, m); 3.27 (2H, m); 4.82(2H, m); 5.89 (1H, m); 6.78 (1H, m); 6.9-7.6 (9H, m); 8.07 (1H, s).

EXAMPLE 46(3S)-3-{5[(E)-3-(Imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzamido}-5-methylsulfanyl-1-phenyl-2-pentanone

The title compound was prepared from pentafluorophenyl5-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoateusing a similar method to that described in Example 3 and isolated asthe hydrochloride salt by treatment with HCl/ether. Yield: 42%

¹H NMR (DMSOd₆+CF₃COOD, 400 MHz) δ: 1.83-2.19 (2H, m); 2.04 (3H, s);2.50-3.07 (6H, m); 3.98 (2H, s); 4.73 (1H, dd); 5.04 (2H, d); 6.46-6.59(1H, m); 6.76 (1H, d); 6.96-7.11 (2H, m); 7.12-7.37 (9H, m); 7.48 (1H,s); 7.74 (1H, s); 7.80 (1H, s); 9.22 (1H, s).

Anal. Calculated for C 64.93 H 5.86 N 6.88 S 5.25 Cl 8.71 C₃₃H₃₄FN₃O₂S,1.5 HCl Found C 66.15 H 6.21 N 6.89 S 5.78 Cl 8.74

MS (ESI) m/z: 556 (MH⁺).

EXAMPLE 471-Methylpiperidin-4-yl(2S)-2-[(3-(4-fluorophenyl)-5-[(E)-3-(1H-imidazol-1-yl)prop-1-enyl]-2-thienylcarbonyl)amino]-4-(methylsulfanyl)butanoate

A solution of1-[3-(4-fluorophenyl)-5-[(E)-3-(1H-imidazol-1-yl)prop-1-enyl]-thien-2-yl]methanoicacid (4.2 g; 12.8 mmol), EDC (3.19 g; 16.6 mmol) and DMAP (0.313 g; 2.6mmol) in DMF (50 ml) was stirred under argon atmosphere for 15 minutes.1-(Methylpiperidin-4-yl)-4-(methylsulfanyl) butanoate (5.27 g; 16.6mmol) and N-methylmorpholine (3.65 ml; 32.2 mmol) were then added. Themixture was stirred at room temperature overnight. After evaporation todryness, the residue was taken up in CH₂Cl₂/H₂O and extracted. Theorganic phase was evaporated and purified by preparative HPLC on reversephase silica eluting with MeOH/(NH₄)2CO₃ buffer (2 g/l, pH 7) 50/50 togive after evaporation of the appropriate fractions a solid which wasredissolved in CH₂Cl₂/ether and treated at 0° C. with a solution ofHCl/ether. After 10 minutes the resulting solid was filtered, washedwith ether and dried to give the desired product. Yield: 14%

¹H NMR (DMSOd₆+TFA, 400 MHz) δ: 1.8-2.2 (6H, m); 2.0 (3H, m); 2.3-2.6(2H, m); 2.78 (3H, s); 2.9-3.2 (2H, m); 3.25-3.5 (2H, m); 4.3-4.5 (1H,m); 4.8-5.2 (2H, m); 5.05 (2H, m); 6.4 (1H, m); 6.8 (1H, d); 7.2-7.6(5H, m); 7.74 (2H, m); 9.2 (1H, s).

Anal. calculated for C 52.23 H 5.78 N 8.61 S 9.31 Cl 11.15C₂₈H₃₃N₄O₃S₂F, 2 HCl, 0.6 H₂O Found C 52.51 H 5.70 N 8.75 S 10.01 Cl11.07

MS (ESI) m/s: 557 (MH⁺).

1-[3-(4-Fluorophhenyl)-5-[(E)-3-(1H-imidazol-1-yl)prop-1-enyl]-thien-2-yl]methanoicAcid

The starting material was prepared as follows:

To a solution of methyl 1-[5-methyl-3-hydroxy-thien-2-yl]methanoate(53.5 g; 0.311 mmol) in pyridine (11), cooled at 0° C. was addeddropwise triflic anhydride (67.83 ml; 0.40 mmol). After stirring at 0°C. for 1 hour and then at room temperature for 1 hour, the mixture wasevaporated to dryness and the residue extracted with CH₂Cl₂/H₂O. Theorganic phase was evaporated and purified by flash chromatography,eluting with petroleum ether/ethylacetate 95/5 to give methyl1-[5-methyl-3-triflate-thien-2-yl]methanoate.

Yield:90%; ¹H NMR (CDCl₃, 400 MHz) δ: 2.51 (3H, s); 3.89 (3H, s); 6.71(1H, s).

To a solution of methyl 1-[5-methyl-3-triflate-thien-2-yl]methanoate (10g; 0.033 mol) in a mixture of toluene (11) and ethanol (100 ml) wasadded 4-fluorobenzene boronic acid (6.9 g; 0.049 mol), Na₂CO₃ 2M (41 ml;0.082 mol), LiCl (2.79 g; 0.066 mol) andtetrakis(triphenylphosphine)palladium(0) (1.52 g; 0.013 mmol). Themixture was refluxed under argon atmosphere for 2 h 30, extracted withethyl acetate and purified by flash chromatography eluting withpetroleum ether/AcOEt 95/5 to give after evaporation and trituration inether to give methyl1-[5-methyl-3-(4-fluorophenyl)-thien-2-yl]methanoate as a white solid.

Yield: 79%; ¹H NMR (CDCl₃, 400 MHz) δ: 2.51 (3H, s); 3.74 (3H, s); 6.75(1H, s); 7.06 (2H, m); 7.40 (2H, m).

A solution of methyl1-[5-methyl-3-(4-fluorophenyl)-thien-2-yl]methanoate (12.9 g; 0.05 mol),N-bromosuccinimide (11.02 g; 0.0619 mol) and 2-2′-azobisisobutyronitrile(0.339 g; 2.06 mmol) in Cl₄ (300 ml) was reflux under argon atmospherefor 90 minutes under UV irradiation. After filtration of theprecipitate, the filtrate was evaporated to dryness to give methyl1-[5-bromomethyl-3-(4-fluorophenyl)-thien-2-yl]methanoate as a solidwhich was used in the next step without purification.

¹H NMR (CDCl₃, 400 MHz) δ: 3.77 (3H, s); 4.65 (2H, s); 7.06 (3H, m);7.40 (2H, m).

A solution of methyl1-[5-bromomethyl-3-(4-fluorophenyl)-thien-2-yl]methanoate (10.6 g; 0.032mol) and triphenylphosphine (8.95 g; 0.035 mol) in toluene (200 ml) wasrefluxed under argon atmosphere for 4 hours. After cooling, theprecipitate was filtered, washed with toluene and petroleum ether anddried to give methyl1-[5-triphenylphosphine-3-(4-fluorophenyl)-thien-2-yl]methanoate.

Yield: 93%; ¹H NMR (CDCl₃, 400 MHz) δ: 3.66 (3H, s); 6.08 (2H, d); 7.05(2H, m); 7.1-7.3 (3H, m); 7.6-8 (15H, m).

To a solution of methyl1-[5-tri-phenylphosphine-3-(4-fluorophenyl)-thien-2-yl]methanoate (17.6g; 0.03 mol) and 2-(imidazol-1-yl)acetaldehyde (8.46 g; 0.06 mol) inCH₂Cl₂ (250 ml was added under argon atmosphere, potassium t-butylate(3.34 g; 0.03 mol). The mixture was stirred at room temperature for 3hours, evaporated and purified by flash chromatography eluting withethyl acetate and then with CH₂Cl₂/MeOH 95/5 to give after triturationin ether methyl1-[5-(3-(1H-imidazol-1-yl)prop-1-enyl)-3-(4-fluorophenyl)-thien-2-yl]methanoatea solid.

Yield: 54%; ¹H NMR (CDCl_(3, 400) MHz) δ: 3.79 (3H, s); 5.0 (2H, d);5.87 (1H, m); 6.72 (1H, m); 6.9-7.8 (8H, m).

A solution of methyl1-[5-[(E)-3-(1H-imidazol-1-yl)prop-1-enyl]-3-(4-fluorophenyl)-thien-2-yl]methanoate(9 g; 0.026 mol) in methanol (100 ml) was treated with 2N aqueous sodiumhydroxide solution (39.5 ml; 0.079 mol). The mixture was heated at 60°C. for 1 hour and evaporated. The residue was taken up in water (100ml)/ether (100 ml). The aqueous phase was acidified with HCl 2N to pH 5and the resulting precipitate was filtered, washed with H₂O, dried overP₂O₅ and triturated in ether to1-[3-(4-fluorophenyl)-5-[(E)-3-(1H-imidazol-1-yl)prop-1-enyl]-thienyl]methanoicacid as a solid.

Yield: 66%; ¹H NMR (CDCl₃, 400 MHz) δ: 6.50 (1H, s); 6.86 (1H, m); 7.25(3H, m); 7.50 (2H, m); 7.74 (1H, m); 7.8 (1H, m); 9.2 (1H, s).

EXAMPLE 48 1-Methylpiperidin-4-yl(2S-[(3-(4-Fluorophenyl-5-[(E)-3-(1H-imidazol-1-yl)prop-1-enyl]-2-thienylcarbonyl)amino]4-(methylsulfanyl)butanoate

The compound was prepared using the same methodology as described forexample 47 but was purified by flash chromatography eluting withCH₂Cl₂/MeOH 98/2.

Yield: 85%; ¹H NMR (CDCl₃, 400 MHz) δ: 1.4 (9H, m); 1.7-2.2 (2H, m);2.03 (3H, s); 2.25 (2H, m); 4.6 (1H, m); 4.7 (2H, m); 6-6.5 (3H, m);6.8-7.6 (8H, m). MS (ESI) m/z: 515 (MH⁺).

EXAMPLE 49(2S)-2-[(3-(4-Fluorophenyl)-5-[(E)-3-(1H-imidazol-1-yl)prop-1-enyl]-2-thienylcarbonyl)amino]-4-(methylsulfanyl)butanoicAcid

A solution of example 48 (2 g; 3.88 mmol) in CH₂Cl₂ (20 ml) was treatedwith TFA (20 ml). The mixture was stirred at room temperature for 2hours. After evaporation, the residue was purified on reverse phasesilica eluting with MeOH/(NH₄)₂ CO₃ buffer (2 g/l, pH 7) 40/60 to givethe desired product. Yield: 33%

¹H NMR (DMSO+CF₃COOD, 400 MHz) δ: 1.8-2.1 (2H, m); 2.01 (3H, s); 2.2-2.5(2H, m); 4.34 (1H, m); 5.02 (2H, d); 6.42 (1H, m); 6.88 (1H, d); 7.1-7.4(3H, m); 7.52 (2H, m); 7.77 (2H, m); 9.19 (1H, s).

Anal. calculated for C 56.57 H 5.36 N 8.53 S 13.02 C₂₂H₂₂N₃O₃S₂F, 0.6H₂O, 0.3 ether Found C 56.28 H 5.10 N 8.71 S 12.76

MS (ESI) m/z: 460 (MH⁺).

What is claimed is:
 1. A compound of Formula (1):

wherein Ar¹ represents:

and wherein R⁵ is hydrogen, C₁₋₄alkyl, phenylC₁₋₄alkyl; R⁶ is hydrogen,C₁₋₄alkyl, hydroxyC₁₋₄alkyl, haloC₁₋₄alkyl, dihaloC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, sulfanylC₁₋₄alkyl, aminoC₁₋₄alkyl,N—(C₁₋₄alkyl)aminoC₁₋₄alkyl, N,N-di(C₁₋₄alkyl)aminoC₁₋₄alkyl orphenylC₁₋₄alkyl; and m is 0, 1 or 2; R¹² and R¹³ are independentlyhydrogen or C₁₋₄alkyl; and Ar² is phenyl, pyridyl, pyridazinyl,pyrimidyl, pyrazinyl, thienyl, thiazolyl, furyl or oxazolyl, the ringbeing substituted on ring carbon atoms by R² and —(CH₂)_(n)R³, whereinAr² is attached to Ar¹C(R¹²)R¹³CH═CH— by a ring carbon atom; or Ar² ispyrrolyl, pyrazolyl or imidazolyl, the ring being substituted on ringcarbon atoms or on the sp³ hybridised ring nitrogen by R² and—(CH₂)_(n)R³, wherein Ar² is attached to Ar¹C(R¹²)R¹³CH═CH— by a ringcarbon atom or the Sp³ hybridised ring nitrogen; and wherein R² is agroup of the Formula (2):

 wherein R⁷ is hydrogen or C₁₋₄alkyl, R⁸ is —(CH₂)_(q)—R¹⁰ wherein q is0-4 and R¹⁰ is C₁₋₄alkylsulfanyl, C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl,hydroxy, C₁₋₄alkoxy, carbamoyl, N—C₁₋₄alkyl carbamoyl,N,N-(diC₁₋₄alkyl)carbamoyl, C₁₋₄alkyl, phenyl, thienyl, orC₁₋₄alkanoylamino, R⁹ is hydroxy, C₁₋₆alkoxy, C₃₋₉cycloalkyloxy,heterocyclyloxy, heterocyclylC₁₋₄alkoxy or —NH—SO₂-R¹¹ wherein R¹¹represents trifluoromethyl, C₁₋₄alkyl, phenyl, heteroaryl, arylC₁₋₄alkylor heteroarylC₁₋₄alkyl; or R² represents a lactone of Formula (3)

the group of Formula (2) or (3) having L or D configuration at thechiral alpha carbon in the corresponding free amino acid; or R² is agroup of the Formula (4): —CONHCH(R¹⁴)R¹⁵  Formula (4)  wherein R¹⁴ is—(CH₂)_(q)—R¹⁶ wherein q is 0-4 and R¹⁶ is C₁₋₄alkylsulfanyl,C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl, hydroxy, C₁₋₄alkoxy, carbamoyl,N—C₁₋₄alkylcarbamoyl, N,N-(diC₁₋₄alkyl)carbamoyl, C₁₋₄alkyl, phenyl,thienyl, or C₁₋₄alkanoylamino; R¹⁵ is of the formula —CH₂OR¹⁷ (whereinR¹⁷ is hydrogen, C₁₋₄alkyl, phenyl, heteroaryl, C₂₋₅alkanoyl,C₁₋₄alkoxymethyl, phenoxymethyl or heteroaryloxymethyl), of the formula—COR¹⁸ or of the formula —CH₂COR¹⁸ (wherein R¹⁸ is C₁₋₄alkyl (optionallysubstituted by halo, cyano, C₂₋₅alkanoyloxy, hydroxy, C₁₋₄alkoxy orC₁₋₄alkanoyl), phenyl, phenylC₁₋₃alkyl, heteroaryl, heteroarylC₁₋₃alkyl,C₅₋₇cycloalkyl, C₅₋₇cycloalkylC₁₋₃alkyl, 2-(phenyl)ethenyl,2-(heteroaryl)ethenyl or N-methoxy-N-methylamino); or R¹⁵ ismorpholinoC₁₋₄alkyl, pyrrolidin-1-ylC₁₋₄alkyl or piperidin-1-ylC₁₋₄alkylwherein the morpholine, pyrrolidine and piperidine rings are optionallysubstituted by C₁₋₄alkyl or C₅₋₇cycloalkyl; or R¹⁵ isphenyl-1-hydroxycC₁₋₄alkyl or heteroaryl-1-hydroxyC₁₋₄alkyl; n is 0, 1or 2; and R³ is phenyl or heteroaryl; and wherein phenyl and heteroarylrings in R³, R⁵, R⁶, R¹¹, R¹⁵ (including R¹⁷ and R¹⁸) are independentlyoptionally substituted on ring carbon atoms by up to three substituentsselected from C₁₋₄alkyl, halogen, hydroxy, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkanoylamino, nitro, cyano,carboxy, thiol, C₁₋₄alkylsulfanyl, C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl,C₁₋₄alkanesulphonamido, N—(C₁₋₄alkylsulphonyl)—N—C₁₋₄alkylamino,aminosulfonyl, N—(C₁₋₄alkyl)aminosulfonyl,N,N-di(C₁₋₄alkyl)aminosulfonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl,N,N-(diC₁₋₄alkyl)carbamoyl, carbamoylC₁₋₄alkyl,N—(C₁₋₄alkyl)carbamoylC₁₋₄alkyl, N,N-(diC₁₋₄alkyl)carbamoylC₁₋₄alkyl,hydroxyC₁₋₄alkyl and C₁₋₄alkoxyC₁₋₄alkyl and on ring NH groups(replacing hydrogen) by C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulfonyl,haloC₁₋₄alkyl, difluoromethyl or trifluoromethyl; or apharmaceutically-acceptable salt, prodrug or solvate thereof.
 2. Acompound of Formula (1):

wherein Ar¹ represents:

and wherein R⁵ is hydrogen, C₁₋₄alkyl, phenylC₁₋₄alkyl; R⁶ is hydrogen,C₁₋₄alkyl, hydroxyC₁₋₄alkyl, haloC₁₋₄alkyl, dihaloC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, sulfanylC₁₋₄alkyl, aminoC₁₋₄alkyl,N—(C₁₋₄alkyl)aminoC₁₋₄alkyl, N,N-di(C₁₋₄alkyl)aminoC₁₋₄alkyl orphenylC₁₋₄alkyl; and m is 0,1 or 2; R¹² and R¹³ are independentlyhydrogen or C₁₋₄alkyl; and Ar² is phenyl, pyridyl or thienyl, the ringbeing substituted on ring carbon atoms by R² and —(CH₂)_(n)R and whereinAr² is attached to Ar¹C(R¹²)R¹³CH═CH— by a ring carbon atom; and whereinR² is a group of the Formula (2):

 wherein R⁷ is hydrogen, R⁸ is —(CH₂)₂—R¹⁰ wherein R¹⁰ isC₁₋₄alkylsulfanyl or C₁₋₄alkylsulfonyl, R⁹ is hydroxy, C₁₋₆alkoxy,C₃₋₉cycloalkyloxy, heterocyclyloxy or heterocyclylC₁₋₄alkoxy; or R²represents a lactone of Formula (3)

the group of Formula (2) or (3) having L or D configuration at thechiral alpha carbon in the corresponding free amino acid; or R² is agroup of the Formula (4): —CONHCH(R¹⁴)R¹⁵  Formula (4)  wherein R¹⁴ is—(CH₂)_(q)—R¹⁶ wherein q is 0-4 and R¹⁶ is C₁₋₄alkylsulfanyl,C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl, hydroxy, C₁₋₄alkoxy, carbamoyl,N—C₁₋₄alkyl carbamoyl, N,N-(diC₁₋₄alkyl)carbamoyl, C₁₋₄alkyl, phenyl,thienyl, or C₁₋₄alkanoylamino; R¹⁵ is of the formula —CH₂OR¹⁷ (whereinR¹⁷ is hydrogen, C₁₋₄alkyl, phenyl, heteroaryl, C₂₋₅alkanoyl,C₁₋₄alkoxymethyl, phenoxymethyl or heteroaryloxymethyl), of the formula—COR¹⁸ or of the formula —CH₂COR¹⁸ (wherein R¹⁸ is C₁₋₄alkyl (optionallysubstituted by halo, cyano, C₂₋₅alkanoyloxy, hydroxy, C₁₋₄alkoxy orC₁₋₄alkanoyl), phenyl, phenylC₁₋₃alkyl, heteroaryl, heteroarylC₁₋₃alkyl,C₅₋₇cycloalkyl, C₅₋₇cycloalkylC₁₋₃alkyl, 2-(phenyl)ethenyl,2-(heteroaryl)ethenyl or N-methoxy-N-methylamino); or R¹⁵ ismorpholinoC₁₋₄alkyl, pyrrolidin-1-ylC₁₋₄alkyl or piperidin-1-ylC₁₋₄alkylwherein the morpholine, pyrrolidine and piperidine rings are optionallysubstituted by C₁₋₄alkyl or C₅₋₇cycloalkyl; or R¹⁵ isphenyl-1-hydroxyC₁₋₄alkyl or heteroaryl-1-hydroxyC₁₋₄alkyl; n is 0, 1 or2; and R³ is phenyl or heteroaryl; and wherein phenyl and heteroarylrings in R³, R⁵, R⁶ and R⁹ are independently optionally substituted onring carbon atoms by up to three substituents selected from C₁₋₄alkyl,halogen, hydroxy, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkanoylamino, nitro, cyano, carboxy, thiol, C₁₋₄alkylsulfanyl,C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄alkanesulphonamido,N—(C₁₋₄alkylsulphonyl)—N—C₁₋₄alkylamino, aminosulfonyl,N—(C₁₋₄alkyl)aminosulfonyl, N,N-di(C₁₋₄alkyl)aminosulfonyl, carbamoyl,N—(C₁₋₄alkyl)carbamoyl, N,N-(diC₁₋₄alkyl)carbamoyl, carbamoylC₁₋₄alkyl,N—(C₁₋₄alkyl)carbamoylC₁₋₄alkyl, N,N-(diC₁₋₄alkyl)carbamoylc C₁₋₄alkyl,hydroxyC₁₋₄alkyl and C₁₋₄alkoxyC₁₋₄alkyl and on ring NH groups(replacing hydrogen) by C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulfonyl,haloC₁₋₄alkyl, difluoromethyl or trifluoromethyl; or apharmaceutically-acceptable salt, prodrug or solvate thereof.
 3. Acompound of Formula (I) as claimed in claim 1 or claim 2 wherein R³ isphenyl.
 4. A compound of Formula (I) as claimed in claim 3 whereinsubstituents on the ring carbon atom(s) of the phenyl ring R³ areselected from C₁₋₄alkyl, halo, trifluoromethyl, C₁₋₄alkoxy, nitro, cyanoand C₁₋₄alkoxyC₁₋₄alkyl.
 5. A compound of Formula (I) as claimed inclaim 4 wherein a carbon atom of the phenyl ring of R³ is substituted byfluoro, chloro or cyano.
 6. A compound of Formula (I) as claimed inclaim 1 or claim 2 wherein n is 0 or
 2. 7. A compound of Formula (I) asclaimed in claim 1 or claim 2 wherein R¹² and R¹³ are hydrogen.
 8. Apharmaceutical composition comprising a compound of Formula (I), or apharmaceutically-acceptable salt thereof, as defined in claim 1 or claim2, with a pharmaceutically-acceptable diluent or carrier.
 9. A method oftreating a disease or medical condition mediated through farnesylationof CAAX-containing proteins which comprises adminstering to awarm-blooded animal in need thereof an effective amount of a compoundaccording to claim 1 or claim 2.